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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 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.

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 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.

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 N‐carbamoyl‐l‐glutamate (NCG), the N‐acetyl‐l‐glutamate analogue used to treat N‐acetylglutamate synthase deficiency, has been proposed as potential therapy of carbamoyl phosphate synthetase 1 deficiency (CPS1D). Previous findings in five CPS1D patients suggest that NCG‐responsiveness could be mutation‐specific. We report on a patient with CPS1D, homozygous for the novel p.(Pro1211Arg) CPS1 mutation, who presented at 9 days of life with hyperammonemic coma which was successfully treated with emergency measures. He remained metabolically stable on merely oral NCG, arginine, and modest protein restriction. Ammonia scavengers were only added after poor dietary compliance following solid food intake at age 1 year. The patient received a liver transplantation at 3.9 years of age, having normal cognitive, motor, and quality of life scores despite repeated but successfully treated episodes of hyperammonemia. Studies using recombinantly produced mutant CPS1 confirmed the partial nature of the CPS1D triggered by the p.(Pro1211Arg) mutation. This mutation decreased the solubility and yield of CPS1 as expected for increased tendency to misfold, and reduced the thermal stability, maximum specific activity (Vmax; ~2‐fold reduction), and apparent affinity (~5‐fold reduction) for ATP of the purified enzyme. By increasing the saturation of the NAG site in vivo, NCG could stabilize CPS1 and minimize the decrease in the effective affinity of the enzyme for ATP. These observations, together with prior experience, support the ascertainment of clinical responsiveness to NCG in CPS1 deficient patients, particularly when decreased stability or lowered affinity for NAG of the mutant enzyme are suspected or proven.

N -carbamoyl-l-glutamate (NCG), the N -acetyl-l-glutamate analogue used to treat N -acetylglutamate synthase deficiency, has been proposed as potential therapy of carbamoyl phosphate synthetase 1 deficiency (CPS1D). Previous findings in five CPS1D patients suggest that NCG-responsiveness could be mutation-specific. We report on a patient with CPS1D, homozygous for the novel p.(Pro1211Arg) CPS1 mutation, who presented at 9 days of life with hyperammonemic coma which was successfully treated with emergency measures. He remained metabolically stable on merely oral NCG, arginine, and modest protein restriction. Ammonia scavengers were only added after poor dietary compliance following solid food intake at age 1 year. The patient received a liver transplantation at 3.9 years of age, having normal cognitive, motor, and quality of life scores despite repeated but successfully treated episodes of hyperammonemia. Studies using recombinantly produced mutant CPS1 confirmed the partial nature of the CPS1D triggered by the p.(Pro1211Arg) mutation. This mutation decreased the solubility and yield of CPS1 as expected for increased tendency to misfold, and reduced the thermal stability, maximum specific activity ( V max ; ~2-fold reduction), and apparent affinity (~5-fold reduction) for ATP of the purified enzyme. By increasing the saturation of the NAG site in vivo, NCG could stabilize CPS1 and minimize the decrease in the effective affinity of the enzyme for ATP. These observations, together with prior experience, support the ascertainment of clinical responsiveness to NCG in CPS1 deficient patients, particularly when decreased stability or lowered affinity for NAG of the mutant enzyme are suspected or proven., Competing Interests: Sufin Yap has received honoraria, travel and accommodation support from Orphan Europe‐Recordati Rare Disease for participation in industry‐sponsored symposia, advisory board meetings, and master classes and attending scientific meetings. Nadine Gougeard, Antony R. Hart, and Belén Barcelona declare that they have no conflict of interest. Vicente Rubio has received honoraria, travel and accommodation from Orphan Europe‐Recordati Rare Disease for participation in company‐sponsored symposia, and advisory board meetings.

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (OMIM 238970) is an autosomal recessive disorder that is caused by a deficiency of mitochondrial ornithine transporter 1, resulting in dysfunction of the urea cycle. HHH is the rarest of the urea cycle disorders, reported in fewer than 100 patients. It is characterized by extreme phenotypic variability, including diverse ages of onset and severity of phenotype. We report the first confirmed instance of HHH syndrome in a premature infant (31 2/7 weeks) with severe hyperammonemia (1,300 μmol/L).This case highlights the importance of considering HHH in the differential diagnosis for neonatal hyperammonemia. Because HHH is not detected by newborn screening, and the characteristic biochemical triad may be subtle or even absent, it has the potential to be underdiagnosed; however, making the diagnosis has critical therapeutic implications as treatment is distinct from other urea cycle defects. For instance, lysine supplementation is a beneficial treatment unique to HHH. Therefore, we present here a review of previously reported cases in order to demonstrate the full spectrum of the disease and highlight potentially diagnostic features.

Introduction: This study is part of the "European network and registry for intoxication type metabolic diseases" (E-IMD) project. Intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders (UCD) and organic acidurias (OA) have a major impact on patients' lives. Patients have to adhere to strict diet and medication and may suffer from metabolic crises and neurocognitive impairment. Disease-specific health-related quality of life (HrQoL) assessment questionnaires are the method of choice to estimate the subjective burden of a disease. To date, no such instrument is available for IT-IEM., Methods: Disease-specific patient- and parent-reported HrQoL questions were constructed in German based on focus group interviews with patients and parents. Questionnaires for patients from 8 to 18 years were piloted with 14 participants (n = 9 children and adolescents, n = 5 parents) by cognitive debriefing and tested psychometrically with 80 participants (n = 38 patients, n = 42 parents) for item characteristics, validity, and reliability to construct the first version of a disease-specific HrQoL questionnaire., Results: Twenty-eight questions were selected based on item descriptives. Scales of self- and proxy questionnaires demonstrated acceptable to excellent reliability in terms of internal consistency (Cronbach's α = 0.70-0.93). Scales and total scores correlated with those of generic HrQoL questionnaires, showing convergent validity., Discussion: The MetabQoL 1.0 questionnaire exhibits sound psychometric properties and is a promising step towards assessing patient-reported outcomes in research and clinical practice. It provides a solid basis for translation into other languages and further elaboration and psychometric exploration in larger populations.

Argininosuccinic acid lyase (ASL) deficiency, caused by mutations in the ASL gene (OMIM: 608310) is a urea cycle disorder that has pleiotropic presentations. On the mild end, ASL deficiency can manifest as nonspecific neurocognitive abnormalities without readily identifiable signs to differentiate it from other causes of intellectual disability or learning disabilities. Dietary management and arginine supplementation, if initiated early, may ameliorate symptoms.Because of the nonspecific nature of the symptoms and the possibility for therapeutic management, ASL deficiency is part of the recommended uniform screening panel for newborn screening in the USA. We report here a case of ASL deficiency that was missed on newborn screening in the USA.The case reported here has two known pathogenic mutations - one with no residual activity and one with reported 10% residual activity. Review of this newborn screening results showed subtle elevation of citrulline, overlapping the normal range. These findings suggest that newborn screening may be missing other patients with ASL deficiency with at least one hypomorphic allele. This case was diagnosed incidentally, but in retrospect had symptoms best attributed in full or in part to his ASA deficiency, including protein aversion, developmental delay, and seizures. This case highlights the importance of considering ASL deficiency in patients with nonspecific abnormal neurocognitive signs, such as epilepsy and developmental delay, even when newborn screening was normal.