This study aimed to analyze the clinical features, genetic basis, and management of late-onset carbamoyl phosphate synthetase 1 deficiency (CPS1D) through a pediatric case report and literature review, highlighting diagnostic challenges and therapeutic strategies. We present a 19-year-old female with recurrent neurological symptoms since age 8. She underwent comprehensive metabolic screening, neuroimaging, and whole-exome sequencing of theCPS1gene. Identified variants were assessed for pathogenicity using multiple orthogonalin silicoprediction tools. The patient's initial hyperammonemic crisis at age 8 was misdiagnosed as encephalitis. Workup at age 13 confirmed hyperammonemia (peak 168 µmol/L), hypocitrullinemia, and elevated glutamine. Genetic analysis identified compound heterozygousCPS1variants: a novel c.1058 T > C (p.F353S) and known pathogenic c.1145C > T (p.P382L). A self-selected low-protein diet controlled acute crises but led to severe growth failure (height 145 cm, weight 30 kg). Late-onset CPS1D's nonspecific neurological symptoms often lead to misdiagnosis. Diagnosis requires a high index of suspicion, integrating metabolic profiling with genetic confirmation. This case expands the pathogenic genotypic spectrum of CPS1D. It crucially highlights that while dietary management is life-saving, it requires expert multidisciplinary oversight to prevent devastating consequences like growth failure, especially in resource-limited settings. Routine ammonia testing in unexplained encephalopathy is paramount.

Base editors can correct disease-causing genetic variants. After a neonate had received a diagnosis of severe carbamoyl-phosphate synthetase 1 deficiency, a disease with an estimated 50% mortality in early infancy, we immediately began to develop a customized lipid nanoparticle-delivered base-editing therapy. After regulatory approval had been obtained for the therapy, the patient received two infusions at approximately 7 and 8 months of age. In the 7 weeks after the initial infusion, the patient was able to receive an increased amount of dietary protein and a reduced dose of a nitrogen-scavenger medication to half the starting dose, without unacceptable adverse events and despite viral illnesses. No serious adverse events occurred. Longer follow-up is warranted to assess safety and efficacy. (Funded by the National Institutes of Health and others.).

Urea cycle disorders (UCDs) are inherited metabolic conditions that lead to inadequate nitrogen detoxification due to defects in urea cycle enzymes or transporters. The severity of UCDs is classified into two types: neonatal onset (severe) and late onset (often milder). This cross-sectional study aimed to assess the levels of intelligence, developmental disabilities, and social functioning in adult patients with UCDs in Japan. A total of 116 adult patients with UCDs were enrolled in the study, including 10 with carbamoyl phosphate synthetase 1 deficiency, 69 with ornithine transcarbamylase deficiency (OTCD), 17 with argininosuccinate synthetase deficiency, 9 with argininosuccinate lyase deficiency, 4 with arginase 1 deficiency, and 7 with Hyperornithinemia-Hyperammonemia-Homocitrullinuria syndrome. Of these, 25 (21.6 %) developed symptoms during the neonatal period (within 28 days after birth), while 86 (74.1 %) presented with symptoms after 28 days of age. The age of onset was unknown in 5 patients. This study included 111 surviving patients and 5 deceased patients (3 with OTCD and 2 with CPS1D). Fifty-three patients (45.7 %) experienced intellectual disabilities, while 48 (41.4 %) had non-intellectual disabilities. Additionally, learning disorders and communication disorders were common among many of the study participants. Sixty patients (51.7 %) graduated from regular high school, and most patients with intellectual disabilities graduated from special education schools. Almost half of the patients (51, 44.0 %) were able to obtain jobs, including simple tasks in supported workplaces, and received compensation for their work. Notably, more patients with OTCD could demonstrate higher social performance including experience of higher education and marriage. However, even OTCD patients without intellectual disabilities often struggled with specific neurobehavioral issues. This study provides information on the social situation of adult UCD patients and underlines the importance for clinicians, as well as society and communities, to understand the ongoing challenges faced by patients with UCDs in order to provide better support.

Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a rare metabolic disorder that, in neonatal onset, is typically characterized by severe life-threatening and neurologically injuring hyperammonemic episodes with high unmet patient need. Patients that retain limited enzyme activity may present later in life with less severe hyperammonemia. CPS1 drives the first step in the urea cycle, the pathway terrestrial mammals utilize to metabolize nitrogen. In order to probe the effect of hyperammonemia on the developing nervous system and explore new therapies, a murine Cps1 exon 3-4 mutant was previously generated. However, these mice die within 24 h of birth, limiting study capabilities. Herein, we developed a novel Cps1 hypomorphic murine model with residual enzyme activity that maintains survival, but with dysfunction of Cps1 that could be detected biochemically. Characterization, based on the orthologous human variant Asn674Ile, revealed that the variant is reproducible, 100% penetrant and biochemically phenocopies the human disorder. The hypomorph presents with elevated ammonia and glutamate, and reduced citrulline, and with an impaired rate of ureagenesis, providing a novel platform to study and develop therapies for CPS1 deficiency.

Carbamoyl phosphate synthetase 1 (CPS1) deficiency (OMIM#237300) is a rare inherited disorder due to complete or partial lack of the CPS1 enzyme. Polymyositis is a relatively rare systemic inflammatory autoimmune disease. Here, we report a 59-year-old Japanese woman diagnosed with late-onset CPS1 deficiency during polymyositis treatment. The polymyositis appeared two years before the diagnosis of CPS1 deficiency. Prednisolone (PSL) at 35 mg/day initial dosage, promptly alleviated the symptoms. However, the patient, without apparent cause, suddenly developed confusion progressing to unconsciousness and coma. Upon admission, the patient's plasma ammonia levels were 458 μg/dL (269 μM). Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels. Genetic analysis of CPS1 (OMIM *608307) showed homozygosity for the likely pathogenic variant c.2397G > A (p.Met799Ile), leading to the diagnosis of CPS1 deficiency. The patient responded to pharmacotherapy and continuous hemodialysis. However, the patient experienced hyperammonemia decompensation events while on pharmacotherapy at home, which were successfully managed with emergency treatment and/or hemodialysis. Subsequently, after liver transplantation, the patient's plasma ammonia levels consistently remained at normal. This case illustrates late-onset CPS1 deficiency manifested in an adult treated with PSL for polymyositis, and the cure of its enzyme deficiency by live-donor liver transplantation.