RESUMO
Urea cycle disorders (UCDs) are a group of rare metabolic conditions characterized by hyperammonemia and a broad spectrum of phenotypic severity. They are caused by the congenital deficiency in the eight biomolecules involved in urea cycle. In the present study, five cases of UCD were recruited and submitted to a series of clinical, biochemical, and genetic analysis with a combination of high throughput techniques. Moreover, in silico analysis was conducted on the identified missense genetic variants. Various clinical and biochemical indications (including profiles of amino acids and urinary orotic acids) of UCD were manifested by the five probands. Sequence analysis revealed nine diagnostic variants, including three novel ones, which caused Argininosuccinic aciduria (ASA) in one case, Carbamoyl phosphate synthetase 1deficiency (CPS1D) in two cases, Ornithine transcarbamylase deficiency (OTCD) in one case, and Citrin deficiency in 1case. Results of in silico biophysical analysis strongly suggested the pathogenicity of each the five missense variants and provided insight into their intramolecular impacts. In conclusion, this study expanded the genetic variation spectrum of UCD, gave solid evidence for counselling to the affected families, and should facilitate the functional study on the proteins in urea cycle.
Assuntos
Simulação por Computador , Mutação de Sentido Incorreto , Ornitina Carbamoiltransferase/genética , Distúrbios Congênitos do Ciclo da Ureia/patologia , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Prognóstico , Distúrbios Congênitos do Ciclo da Ureia/etiologia , Distúrbios Congênitos do Ciclo da Ureia/metabolismoRESUMO
BACKGROUND: Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare urea cycle disorder. The aim of this study was to present the clinical findings, management, biochemical data, molecular genetic analysis, and short-term prognosis of five children with CPS1D. METHODS: The information of five CPS1D patients was retrospectively studied. We used targeted next-generation sequencing to identify carbamoyl phosphate synthetase 1 (CPS1) variants in patients suspected to have CPS1D. Candidate mutations were validated by Sanger sequencing. In silico and structure analyses were processed for the pathogenicity predictions of the identified mutations. RESULTS: The patients had typically clinical manifestations and biochemical data of CPS1D. Genetic analysis revealed nine mutations in the CPS1 gene, including recurrence of c.1145C > T, five of which were firstly reported. Seven mutations were missense changes, while the remaining two were predicted to create premature stop codons. In silico and structure analyses showed that these genetic lesions were predicted to affect the function or stability of the enzyme. CONCLUSION: We reported five cases of CPS1D. Five novel mutations of CPS1 gene were found. Mutations of CPS1 have private nature, and most of them are missense compound heterozygous. The mutation affecting residue predicted to interfere the catalytic sites, the internal tunnel, or the regulatory domain results in severe phenotype.
Assuntos
Carbamoil-Fosfato Sintase (Amônia)/genética , Doença da Deficiência da Carbamoil-Fosfato Sintase I/etiologia , Mutação , Doença da Deficiência da Carbamoil-Fosfato Sintase I/diagnóstico por imagem , Doença da Deficiência da Carbamoil-Fosfato Sintase I/psicologia , Doença da Deficiência da Carbamoil-Fosfato Sintase I/terapia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
The urea cycle and glutamine synthetase (GS) are the two main pathways for waste nitrogen removal and their deficiency results in hyperammonemia. Here, we investigated the efficacy of liver-specific GS overexpression for therapy of hyperammonemia. To achieve hepatic GS overexpression, we generated a helper-dependent adenoviral (HDAd) vector expressing the murine GS under the control of a liver-specific expression cassette (HDAd-GS). Compared to mice injected with a control vector expressing an unrelated reporter gene (HDAd-alpha-fetoprotein), wild-type mice with increased hepatic GS showed reduced blood ammonia levels and a concomitant increase of blood glutamine after intraperitoneal injections of ammonium chloride, whereas blood urea was unaffected. Moreover, injection of HDAd-GS reduced blood ammonia levels at baseline and protected against acute hyperammonemia following ammonia challenge in a mouse model with conditional hepatic deficiency of carbamoyl phosphate synthetase 1 (Cps1), the initial and rate-limiting step of ureagenesis. In summary, we found that upregulation of hepatic GS reduced hyperammonemia in wild-type and Cps1-deficient mice, thus confirming a key role of GS in ammonia detoxification. These results suggest that hepatic GS augmentation therapy has potential for treatment of both primary and secondary forms of hyperammonemia.
Assuntos
Amônia/metabolismo , Terapia Genética/métodos , Glutamato-Amônia Ligase/genética , Hiperamonemia/genética , Hiperamonemia/terapia , Fígado/metabolismo , Amônia/toxicidade , Animais , Carbamoil-Fosfato Sintase (Amônia)/genética , Carbamoil-Fosfato Sintase (Amônia)/metabolismo , Doença da Deficiência da Carbamoil-Fosfato Sintase I/genética , Doença da Deficiência da Carbamoil-Fosfato Sintase I/metabolismo , Doença da Deficiência da Carbamoil-Fosfato Sintase I/terapia , Modelos Animais de Doenças , Feminino , Técnicas de Transferência de Genes , Glutamato-Amônia Ligase/metabolismo , Hiperamonemia/metabolismo , Hiperamonemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Especificidade de Órgãos/genéticaRESUMO
BACKGROUND: Carbamoyl Phosphate Synthetase 1 deficiency (CPS1D) is a rare autosomal recessive inborn metabolic disease characterized mainly by hyperammonemia. The fatal nature of CPS1D and its similar symptoms with other urea cycle disorders (UCDs) make its diagnosis difficult, and the molecular diagnosis is hindered due to the large size of the causative gene CPS1. Therefore, the objective of the present study was to investigate the clinical applicability of exome sequencing in molecular diagnosis of CPS1D in Chinese population. METHODS: We described two Chinese neonates presented with unconsciousness and drowsiness due to deepening encephalopathy with hyperammonemia. Whole exome sequencing was performed. Candidate mutations were validated by Sanger sequencing. In-silicon analysis was processed for the pathogenicity predictions of the identified mutations. RESULTS: Two compound heterozygous mutations in the gene carbamoyl phosphate synthetase 1(CPS1) were identified. One is in Case 1 with two novel missense mutations (c.2537C>T, p. Pro846Leu and c.3443T>A, p.Met1148Lys), and the other one is in Case 2 with a novel missense mutation (c.1799G>A, p.Cys600Tyr) and a previously reported 12-bp deletion (c.4088_4099del, p.Leu 1363_Ile1366del). Bioinformatics deleterious predictions indicated pathogenicity of the missense mutations. Conversation analysis and homology modeling showed that the substituted amino acids were highly evolutionary conserved and necessary for enzyme stability or function. CONCLUSION: The present study initially and successfully applied whole exome sequencing to the molecular diagnosis of CPS1D in Chinese neonates, indicating its applicability in cost-effective molecular diagnosis of CPS1D. Three novel pathogenic missense mutations were identified, expanded the mutational spectrum of the CPS1 gene.
Assuntos
Carbamoil-Fosfato Sintase (Amônia)/genética , Doença da Deficiência da Carbamoil-Fosfato Sintase I/diagnóstico , Doença da Deficiência da Carbamoil-Fosfato Sintase I/genética , Sequenciamento do Exoma/métodos , Técnicas de Diagnóstico Molecular/métodos , Feminino , Humanos , Recém-Nascido , Masculino , Modelos Moleculares , Mutação/genéticaRESUMO
BACKGROUND: Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive disorder of the urea cycle, mostly characterized by hyperammonemia and the concomitant leukodystrophy. The onset of CPS1D can be at any age, and the clinical manifestations are variable and atypical. Genetic tests are indispensable for accurate diagnosis of CPS1D on the basis of biochemical tests. METHODS: Blood tandem mass spectrometric analysis and urea organic acidemia screening were performed on a Chinese neonatal patient with low activity, recurrent seizures, and hyperammonemia. Next-generation sequencing and Sanger sequencing were followed up for making a definite diagnosis. Bioinformatics tools were used for the conservation analysis and pathogenicity predictions of the identified mutations. RESULTS: Increased lactate in urea and decreased citrulline in blood were detected in the patient. Two novel mutations (c.173G>T, p.G58V in exon 2 and c.796G>A, p.G266R in exon 8) in CPS1 identified in the neonatal patient were found through coseparation verification. Both of the two mutations were predicted to be deleterious, and the two relevant amino acids exerted highly evolutionarily conserved. The final diagnosis of the patient was compound heterozygous CPS1D. CONCLUSION: This study described the specific clinical characteristics and the variations of physiological and biochemical indices in a Chinese neonatal patient with CPS1D, which facilitated the diagnosis and mechanism research of the disease. Two novel causative missense mutations were identified, which enriched the mutation spectrum of CPS1D in China and worldwide. Advice of prenatal diagnosis was given to the family for a new pregnancy.
Assuntos
Carbamoil-Fosfato Sintase (Amônia)/genética , Doença da Deficiência da Carbamoil-Fosfato Sintase I/complicações , Doença da Deficiência da Carbamoil-Fosfato Sintase I/genética , Hiperamonemia/etiologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/etiologia , Mutação/genética , Carbamoil-Fosfato Sintase (Amônia)/metabolismo , Análise Mutacional de DNA , Saúde da Família , Feminino , Genótipo , Humanos , Masculino , Modelos Moleculares , Espectrometria de Massas em TandemRESUMO
OBJECTIVES: Carbamoyl phosphate synthetase 1 (CPS-1) deficiency is a rare urea cycle disorder with an estimated prevalence of one in 150,000-200,000 live births. Patients often present with hyperammonemia shortly after protein feeding in the early days of life, and early-onset type is associated with high mortality rate. CASE PRESENTATION: We present here a case of a newborn male with a history of two deceased siblings whose ammonium level exceeded 200⯵mol/L on the first day after birth, and who was started on dextrose infusion and ammonia-scavenging therapy after oral feeding was discontinued. Peritoneal dialysis was initiated after the patient's ammonia level exceeded 500⯵mol/L. At the age of five months, the patient underwent hemodialysis due to elevated ammonia levels accompanied by lethargy. The patient's ammonia levels were successfully brought under control, and the patient underwent a liver transplantation at the age of six month, donated by the father. CONCLUSIONS: We present this case to emphasize the efficacy of liver transplantation from a parent carrying a CPS-1 deficiency. The authors believe that, with further support from future studies, the use of carglumic acid can improve the prognosis in the chronic management of CPS-1 deficiency.
RESUMO
OBJECTIVES: Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a severe urea cycle disorder. Patients can present with hyperammonemic coma in the first days of life. Treatment includes nitrogen scavengers, reduced protein intake and supplementation with L-arginine and/or L-citrulline. N-carbamoyl glutamate (NCG) has been hypothesized to stimulate the residual CPS1 function, although only few patients are reported. CASE PRESENTATION: We report a patient with neonatal-onset CPS1 deficiency who received NCG in association with nitrogen scavenger and L-citrulline. The patient carried the novel variants CPS1-c.2447A>G p.(Gln816Arg) and CPS1-c.4489T>C p.(Tyr1497His). The latter is localized in the C-terminal allosteric domain of the protein, and is implicated in the binding of the natural activator N-acetyl-L-glutamate. NCG therapy was effective in controlling ammonia levels, allowing to increase the protein intake. CONCLUSIONS: Our data show that the response to NCG can be indicated based on the protein structure. We hypothesize that variants in the C-terminal domain may be responsive to NCG therapy.
Assuntos
Doença da Deficiência da Carbamoil-Fosfato Sintase I , Distúrbios Congênitos do Ciclo da Ureia , Humanos , Recém-Nascido , Carbamoil-Fosfato Sintase (Amônia)/química , Carbamoil-Fosfato Sintase (Amônia)/metabolismo , Doença da Deficiência da Carbamoil-Fosfato Sintase I/metabolismo , Doença da Deficiência da Carbamoil-Fosfato Sintase I/terapia , Citrulina/uso terapêutico , Ácido GlutâmicoRESUMO
Carbamoyl-phosphate synthetase 1 (CPS1) deficiency is an autosomal recessive congenital urea cycle disorder (UCD) characterized by hyperammonemia. The recipients of liver transplantation (LT) for UCD are often children, and the potential donors are often the parents. Hereditary congenital diseases involving UCD entail the possibility of both parents being genetically heterozygous. Herein, we describe the case of a 12-year-old girl with CPS1 deficiency receiving a liver transplant (soon after birth) from her father, who had a heterozygous CPS1 mutation. She was referred to our hospital with respiratory distress after contracting two infections (respiratory syncytial virus and human metapneumovirus) within a short period, both of which presented with hyperammonemia. Medication for hyperammonemia quickly lowered the ammonia levels. The hyperammonemia was thought to be caused by the heterozygous mutation in the donor liver; moreover, it is likely that the low enzyme activity in the patient's liver was increased due to the infections. This is the first study to report hyperammonemia in a CPS1 deficiency patient due to an infection after LT. Thus, patients with CPS1 deficiency should be aware of the development of hyperammonemia after LT.
RESUMO
PURPOSE: Carbamoyl phosphate synthetase 1 (CPS1) deficiency affects the first step of urea cycle and is a severe form of urea cycle disorder (UCD). The severity of hyperammonemic encephalopathy determines the clinical course of UCDs. Here, we describe the genetic and clinical characteristics of CPS1 deficiency in Korea. PATIENT AND METHODS: This study included seven patients with CPS1 deficiency genetically confirmed from January 1992 to September 2020. The peak ammonia level during the first crisis, the half time of peak ammonia level, the initial plasma amino acid levels, and neurological outcomes were compared between CPS1 deficiency and two common UCDs (i.e., 17 patients with argininosuccinate synthetase 1 deficiency and 24 patients with ornithine transcarbamylase deficiency). RESULT: Eleven CPS1 mutations were identified, including 10 novel mutations. Eight mutations were missense. Six patients with CPS1 deficiency had neonatal type. The peak ammonia level, initial glutamate level, and accompanying rate of irreversible neurological damages were highest in patients with CPS1 deficiency. The patient with late-onset CPS1 deficiency responded dramatically to N-carbamylglutamate treatment. CONCLUSION: The clinical manifestations of CPS1 deficiency were the most severe among UCDs. Considering the high proportion of missense mutations, responsiveness to N-carbamylglutamate would be evaluated in a future study.
Assuntos
Carbamoil-Fosfato Sintase (Amônia) , Doença da Deficiência da Carbamoil-Fosfato Sintase I , Distúrbios Congênitos do Ciclo da Ureia , Carbamoil-Fosfato Sintase (Amônia)/deficiência , Carbamoil-Fosfato Sintase (Amônia)/genética , Doença da Deficiência da Carbamoil-Fosfato Sintase I/diagnóstico , Doença da Deficiência da Carbamoil-Fosfato Sintase I/genética , Carbamoil-Fosfato , Humanos , Recém-Nascido , Mutação , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Distúrbios Congênitos do Ciclo da Ureia/genéticaRESUMO
Carbamoyl phosphate synthetase 1 (CPS1) deficiency is an autosomal recessive urea cycle disorder with varying presentations. Patients with a neonatal-onset phenotype are initially healthy but develop severe hyperammonemia days after birth and often have poor or lethal outcomes, while patients who present later in life may exhibit less severe clinical manifestations. CPS1 deficiency is rarely found on newborn screening because most states do not screen for this disease due to the technical difficulties. We report a case of an 11-year-old, previously healthy girl who presented with hyperammonemia and acute psychosis after eating large amounts of meat at summer camp. A diagnosis of carbamoyl phosphate synthetase type 1 deficiency was suspected by biochemical profiles and confirmed by molecular analysis. Subsequent follow up lab results revealed ammonia to be only 25-39 µmol/L shortly after glutamine reached levels as high as 770-1432 µmol/L with concurrent alanine elevations, highlighting the compensating mechanisms of the human body. Her initial hospital course also demonstrated the importance of continuous renal replacement therapy (CRRT) in avoiding rebound hyperammonemia and high glutamine and the benefits of intracranial pressure (ICP) monitoring, providing 3% hypertonic saline and temperature control to avoid fever in treating cerebral edema. Carglumic acid was not considered helpful in this case, with BUN levels ranging between 2 and 4 mg/dL after administration.
RESUMO
Background: Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder characterized by hyperammonaemia. The biochemical measurement of the intermediate metabolites is helpful for CPS1D diagnosis; it however cannot distinguish CPS1D from N-acetylglutamate synthetase deficiency. Therefore, next-generation sequencing (NGS) is often essential for the accurate diagnosis of CPS1D. Methods: NGS was performed to identify candidate gene variants of CPS1D in a Asian neonatal patient presented with poor feeding, reduced activity, tachypnea, lethargy, and convulsions. The potential pathogenicity of the identified variants was predicted by various types of bioinformatical analyses, including evolution conservation, domain and 3D structure simulations. Results: Compound heterozygosity of CPS1D were identified. One was in exon 24 with a novel heterozygous missense variant c.2947C > T (p.P983S), and another was previously reported in exon 20 with c.2548C > T (p.R850C). Both variants were predicted to be deleterious. Conservation analysis and structural modeling showed that the two substituted amino acids were highly evolutionarily conserved, resulting in potential decreases of the binding pocket stability and the partial loss of enzyme activity. Conclusion: In this study, two pathogenic missense variants were identified with NGS, expanding the variants pectrum of the CPS1 gene. The variants and related structural knowledge of CPS enzyme demonstrate the applicability for the accurate diagnosis of CPS1D.
RESUMO
Proximal urea cycle disorders (PUCDs) have adverse outcomes such as intellectual disability and death, which may benefit from newborn screening (NBS) through early detection and prevention with early treatment. Ornithine transcarbamylase deficiency (OTCD) and carbamoyl phosphate synthetase 1 deficiency (CPS1D) are screened in six and eight states in the United States. We analyzed current evidence to see if it supports inclusion of PUCDs in the NBS panels based upon prevention potential, medical, diagnostic, treatment, and public health rationales. A literature review was performed in PubMed using MESH terms for OTCD, CPS1D, and NAGSD. A systematic review was performed in the hallmark of NBS inclusion criteria. We reviewed 31 articles. Molecular and biochemical diagnosis is available to provide diagnostic evidence. Untreated PUCDs have a significant burden with considerable developmental delay and mortality that may improve with early treatment. Tandem mass spectrometry can be used for NBS for PUCDs; however, citrulline and glutamine alone are not specific. Medical treatments currently available for PUCDs meet existing medical, diagnostic, treatment, and public health rationales. Improvement in NBS algorithms to increase sensitivity and specificity will allow earlier diagnosis and treatment to potentially improve disability and mortality rates.
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Carbamoyl phosphate synthetase I (CPS1) deficiency (CPS1D), is a rare autosomal recessive disorder, characterized by life-threatening hyperammonemia. In this study, we presented the detailed clinical features and genetic analysis of two patients with neonatal-onset CPS1D carrying two compound heterozygous variants of c.1631C > T (p.T544M)/c.1981G > T (p.G661C), and c.2896G > T (p.E966X)/c622-3C > G in CPS1 gene, individually. Out of them, three variants are novel, unreported including a missense (c.1981G > T, p.G661C), a nonsense (c.2896G > T, p.E966X), and a splicing change of c.622-3C > G. We reviewed all available publications regarding CPS1 mutations, and in total 264 different variants have been reported, with majority of 157 (59.5%) missense, followed by 35 (13.2%) small deletions. This study expanded the mutational spectrum of CPS1. Moreover, our cases and review further support the idea that most (≥90%) of the mutations were "private" and only â¼10% recurred in unrelated families.
RESUMO
Diagnosis of the urea cycle disorder (USD) carbamoyl-phosphate synthetase 1 (CPS1) deficiency (CPS1D) based on only the measurements of biochemical intermediary metabolites is not sufficient to properly exclude other UCDs with similar symptoms. We report the first Korean CPS1D patient using whole exome sequencing (WES). A four-day-old female neonate presented with respiratory failure due to severe metabolic encephalopathy with hyperammonemia (1,690 µmol/L; reference range, 11.2-48.2 µmol/L). Plasma amino acid analysis revealed markedly elevated levels of alanine (2,923 µmol/L; reference range, 131-710 µmol/L) and glutamine (5,777 µmol/L; reference range, 376-709 µmol/L), whereas that of citrulline was decreased (2 µmol/L; reference range, 10-45 µmol/L). WES revealed compound heterozygous pathogenic variants in the CPS1 gene: one novel nonsense pathogenic variant of c.580C>T (p.Gln194*) and one known pathogenic frameshift pathogenic variant of c.1547delG (p.Gly516Alafs*5), which was previously reported in Japanese patients with CPS1D. We successfully applied WES to molecularly diagnose the first Korean patient with CPS1D in a clinical setting. This result supports the clinical applicability of WES for cost-effective molecular diagnosis of UCDs.
Assuntos
Carbamoil-Fosfato Sintase (Amônia)/genética , Doença da Deficiência da Carbamoil-Fosfato Sintase I/genética , Sequência de Bases , Carbamoil-Fosfato Sintase (Amônia)/química , Doença da Deficiência da Carbamoil-Fosfato Sintase I/diagnóstico , Códon sem Sentido , Éxons , Feminino , Mutação da Fase de Leitura , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , República da Coreia , Análise de Sequência de DNA , Distúrbios Congênitos do Ciclo da Ureia/diagnósticoRESUMO
BACKGROUND: Urea cycle disorders (UCDs) are rare inherited metabolic defects of ammonia detoxification. In about half of patients presenting with a UCD, the first symptoms appear within a few days after birth. These neonatal onset patients generally have a severe defect of urea cycle function and their survival and outcome prognoses are often limited. To understand better the current situation of neonatal onset in UCDs, we have performed a multicentre, retrospective, non-interventional case series study focussing on the most severe UCDs, namely defects of carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), and argininosuccinate synthetase (ASS). METHODS AND RESULTS: Data of 63 patients were collected (27 patients with ASS deficiency, 23 patients with OTC deficiency, and 12 patients with CPS1 deficiency, one patient definite diagnosis not documented). The majority of patients (43/63, 68 %) had an initial ammonia concentration exceeding 500 µmol/L (normal < 100), of which most (26/43, 60.5 %) were also encephalopathic and were treated with hemodialysis. In patients surviving the initial crisis, recurrence of hyperammonemic events within the first 1.5 years of life occurred frequently (mean 3.6 events, range 0-20). Of all patients, 16 (25.4 %) died during or immediately after the neonatal period. CONCLUSION: We observed in this cohort of neonatal onset UCD patients a high rate of initial life-threatening hyperammonemia and a high risk of recurrence of severe hyperammonemic crises. These corresponded to a high mortality rate during the entire study period (30.2 %) despite the fact that patients were treated in leading European metabolic centers. This underlines the need to critically re-evaluate the current treatment strategies in these patients.
Assuntos
Hiperamonemia/patologia , Distúrbios Congênitos do Ciclo da Ureia/patologia , Arginina/uso terapêutico , Pré-Escolar , Feminino , Humanos , Hiperamonemia/tratamento farmacológico , Hiperamonemia/mortalidade , Hiperamonemia/cirurgia , Lactente , Estimativa de Kaplan-Meier , Transplante de Fígado , Masculino , Doença da Deficiência de Ornitina Carbomoiltransferase/tratamento farmacológico , Doença da Deficiência de Ornitina Carbomoiltransferase/mortalidade , Doença da Deficiência de Ornitina Carbomoiltransferase/patologia , Doença da Deficiência de Ornitina Carbomoiltransferase/cirurgia , Prognóstico , Estudos Retrospectivos , Benzoato de Sódio/uso terapêutico , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Distúrbios Congênitos do Ciclo da Ureia/mortalidade , Distúrbios Congênitos do Ciclo da Ureia/cirurgiaRESUMO
Diagnosis of the urea cycle disorder (USD) carbamoyl-phosphate synthetase 1 (CPS1) deficiency (CPS1D) based on only the measurements of biochemical intermediary metabolites is not sufficient to properly exclude other UCDs with similar symptoms. We report the first Korean CPS1D patient using whole exome sequencing (WES). A four-day-old female neonate presented with respiratory failure due to severe metabolic encephalopathy with hyperammonemia (1,690 µmol/L; reference range, 11.2-48.2 µmol/L). Plasma amino acid analysis revealed markedly elevated levels of alanine (2,923 µmol/L; reference range, 131-710 µmol/L) and glutamine (5,777 µmol/L; reference range, 376-709 µmol/L), whereas that of citrulline was decreased (2 µmol/L; reference range, 10-45 µmol/L). WES revealed compound heterozygous pathogenic variants in the CPS1 gene: one novel nonsense pathogenic variant of c.580C>T (p.Gln194*) and one known pathogenic frameshift pathogenic variant of c.1547delG (p.Gly516Alafs*5), which was previously reported in Japanese patients with CPS1D. We successfully applied WES to molecularly diagnose the first Korean patient with CPS1D in a clinical setting. This result supports the clinical applicability of WES for cost-effective molecular diagnosis of UCDs.