1.         题目：Brimble, E. and M. R. Z. Ruzhnikov . "Metabolic Disorders Presenting with Seizures in the Neonatal Period."

索引：Seminars in Neurology,2020,40(2): 219-235.

摘要：Metabolic disorders represent rare but often treatable causes of seizures and epilepsy of neonatal onset. As seizures are relatively common in the neonatal period, systemic clues to a specific diagnosis may be lacking or shrouded by acute illness. An important role of the consulting pediatric neurologist is to identify neonates with a possible metabolic or otherwise genetic diagnosis. In this review, the authors describe presenting signs and symptoms, a diagnostic framework, and disorder-specific treatment options for inborn errors of metabolism that may present in the neonatal period. Specific attention is given to the neurologic aspects of each condition, including the electroclinical phenotype and findings on brain imaging. As expedited diagnosis and prompt initiation of available therapies have been demonstrated to result in improved epilepsy and developmental outcomes, this work acts as a framework to guide evaluation when an inherited metabolic disorder is suspected. In addition to informing treatment, a definitive diagnosis allows for appropriate counseling regarding prognosis, any associated screening or preventive measures, and family planning.

2.         题目：Untargeted metabolomic profiling reveals multiple pathway perturbations and new clinical biomarkers in urea cycle disorders.

索引：Genetics in Medicine,2019, 21(9): 1977-1986.

摘要：PURPOSE: Untargeted metabolomic analysis is increasingly being used in the screening and management of individuals with inborn errors of metabolism (IEM). We aimed to test whether untargeted metabolomic analysis in plasma might be useful for monitoring the disease course and management of urea cycle disorders (UCDs).METHODS: Untargeted mass spectrometry-based metabolomic analysis was used to generate z-scores for more than 900 metabolites in plasma from 48 individuals with various UCDs. Pathway analysis was used to identify common pathways that were perturbed in each UCD.RESULTS: Our metabolomic analysis in plasma identified multiple potentially neurotoxic metabolites of arginine in arginase deficiency and, thus, may have utility in monitoring the efficacy of treatment in arginase deficiency. In addition, we were also able to detect multiple biochemical perturbations in all UCDs that likely reflect clinical management, including metabolite alterations secondary to dietary and medication management.CONCLUSION: In addition to utility in screening for IEM, our results suggest that untargeted metabolomic analysis in plasma may be beneficial for monitoring efficacy of clinical management and off-target effects of medications in UCDs and potentially other IEM.

3.         题目：Institutional experience of newborn screening for inborn metabolism disorders by tandem MS in the Turkish population.

索引：Journal of Pediatric Endocrinology and Metabolism,2020,33(6): 703-711.

摘要：The tandem mass spectrometry method in the screening of congenital metabolic disorders is not included in routine national newborn screening programmes in Turkey. To evaluate the distribution of acylcarnitines and amino acid levels in normal newborns, establish acylcarnitine and amino acid cut-off levels and further preliminary results of inherited metabolic disorders inferentially in the Turkish population. Newborn screening tests performed by tandem MS from 2016 to 2018 were retrospectively reviewed. The study group included 17,066 newborns born in our hospitals located in various regions of Turkey. Blood samples were obtained from infants older than 24 h of age. Among the 17,066 newborns, the metabolic screening data of 9,994 full-term newborns (>37 weeks) were employed to obtain the percentile distribution of the normal population. The study group (17,066) was screened for 26 types of inborn error of metabolism. Our established cut-offs, were compared with the cut-offs determined by Region for Stork Study and Centers for Disease Control. Among the 26 screened disorders, a total of 12 cases (8 amino acid metabolism disorders, 1 urea cycle defect, 2 organic acidaemias and 1 fatty acid oxidation disorder) were identified. Because of the high rate of consanguineous marriages in Turkey, the development of a nationwide screening panel is necessary for early detection and management of potentially treatable inherited metabolic disorders.

4.         题目：Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations.

索引： Human Mutation ,2017,38(5): 471-484.

摘要：Citrullinemia type 1 is an autosomal recessive urea cycle disorder caused by defects in the argininosuccinate synthetase (ASS) enzyme due to mutations in ASS1 gene. An impairment of ASS function can lead to a wide spectrum of phenotypes, from life-threatening neonatal hyperammonemia to a later onset with mild symptoms, and even some asymptomatic patients exhibiting an only biochemical phenotype. The disease is panethnic. In this update, we report 137 mutations (64 of which are novel), consisting of 89 missense mutations, 19 nonsense mutations, 17 mutations that affect splicing, and 12 deletions. The change p.Gly390Arg is by far the most common mutation and is widely spread throughout the world. Other frequent mutations (p.Arg157His, p.Trp179Arg, p.Val263Met, p.Arg304Trp, p.Gly324Ser, p.Gly362Val, and p.Arg363Trp), each found in at least 12 independent families, are mainly carried by patients from the Indian subcontinent, Turkey, Germany, and Japan. To better understand the disease, we collected clinical data of >360 patients, including all published information available. This information is related to the patients' genetic background, the conservation of the mutated residues and a structural rationalization of the effect of the most frequent mutations. In addition, we review ASS regulation, animal models, diagnostic strategies, newborn screening, and treatment options.

5.         题目：Generation of a human induced pluripotent stem cell line (SDQLCHi036-A) from a patient with ornithine transcarbamylase deficiency carrying a deletion involving 3-9 exons of OTC gene.

索引： Stem Cell Research 52 (no pagination), 2021,Date of Publication: April 2021.

摘要：Ornithine transcarbamylase deficiency (OTCD) is a rare X-linked urea cycle disorder. Maternal OTCD can lead to life-threatening hyperammonemia if untreated. Here, we report the Generation of an iPSC line from a patient with OTCD carrying a deletion involving 3-9 exons of OTC gene using non-integrating plasmids expressing OCT4, SOX2, c-MYC, KLF4, and BCL-XL. The SDQLCHi036-A showed normal karyotype, pluripotent state, and potential to differentiate into three germ layers. Our approach offers a useful model to explore pathogenesis and therapy of OTCD.

6.         题目：Noncoding sequence variants define a novel regulatory element in the first intron of the N-acetylglutamate synthase gene.

索引：Human Mutation,2021,doi: 10.1002/humu.24281.

摘要：N-acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder caused either by decreased expression of the NAGS gene or defective NAGS enzyme resulting in decreased production of N-acetylglutamate (NAG), an allosteric activator of carbamylphosphate synthetase 1 (CPS1). NAGSD is the only urea cycle disorder that can be effectively treated with a single drug, N-carbamylglutamate (NCG), a stable NAG analog, which activates CPS1 to restore ureagenesis. We describe three patients with NAGSD due to four novel noncoding sequence variants in the NAGS regulatory regions. All three patients had hyperammonemia that resolved upon treatment with NCG. Sequence variants NM_153006.2:c.427-222G>A and NM_153006.2:c.427-218A>C reside in the 547 bp-long first intron of NAGS and define a novel NAGS regulatory element that binds retinoic X receptor alpha. Sequence variants NC_000017.10:g.42078967A>T (NM_153006.2:c.-3065A>T) and NC_000017.10:g.42078934C>T (NM_153006.2:c.-3098C>T) reside in the NAGS enhancer, within known HNF1 and predicted glucocorticoid receptor binding sites, respectively. Reporter gene assays in HepG2 and HuH-7 cells demonstrated that all four substitutions could result in reduced expression of NAGS. These findings show that analyzing noncoding regions of NAGS and other urea cycle genes can reveal molecular causes of disease and identify novel regulators of ureagenesis.

7.         题目：Disease-causing mutations in the promoter and enhancer of the ornithine transcarbamylase gene.

索引：Human Mutation,2018, 39(4): 527-536.

摘要：The ornithine transcarbamylase (OTC) gene is on the X chromosome and its product catalyzes the formation of citrulline from ornithine and carbamylphosphate in the urea cycle. About 10%-15% of patients, clinically diagnosed with OTC deficiency (OTCD), lack identifiable mutations in the coding region or splice junctions of the OTC gene on routine molecular testing. We collected DNA from such patients via retrospective review and by prospective enrollment. In nine of 38 subjects (24%), we identified a sequence variant in the OTC regulatory regions. Eight subjects had unique sequence variants in the OTC promoter and one subject had a novel sequence variant in the OTC enhancer. All sequence variants affect positions that are highly conserved in mammalian OTC genes. Functional studies revealed reduced reporter gene expression with all sequence variants. Two sequence variants caused decreased binding of the HNF4 transcription factor to its mutated binding site. Bioinformatic analyses combined with functional assays can be used to identify and authenticate pathogenic sequence variants in regulatory regions of the OTC gene, in other urea cycle disorders or other inborn errors of metabolism.

8.         题目：Retrospective evaluations revealed pre-symptomatic citrulline concentrations measured by newborn screening were significantly low in late-onset ornithine transcarbamylase deficiency patients.

索引： Clinica Chimica Acta,2020,510(pp 633-637).

摘要：Introduction: Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. Late-onset OTCD manifests after the neonatal period; therefore, if pre-symptomatic diagnosis and treatment are performed, it can improve the prognosis by preventing hyperammonemia. However, pre-symptomatic diagnosis is unreliable as the specific screening marker of OTCD has not been established yet. This retrospective study aimed to evaluate the pre-symptomatic blood citrulline levels in patients with late-onset OTCD.Methods: Patients with late-onset OTCD who were born after the newborn screening based on tandem mass spectrometry (MS/MS-NBS) was started and were referred to Hyogo College of Medicine Hospital between 2014 and 2018 were included. Pre-symptomatic blood citrulline levels measured by MS/MS-NBS were retrospectively evaluated.Results: Four patients were included in this study. The pre-symptomatic blood citrulline levels were 2.02, 4.50, 4.97, and 3.75 µmol/l, respectively. Compared with the citrulline levels in all newborns in Hyogo prefecture, these values were significantly low.Conclusions: These results suggest the possibility that hypocitrullinemia detected by the MS/MS-NBS can be used as a screening marker for some patients with late-onset OTCD. Further retrospective evaluation of pre-symptomatic citrulline levels in patients with late-onset OTCD, as well as prospective monitoring of hypocitrullinemia on the MS/MS-NBS should be conducted.

9.         题目：Two cases of carbonic anhydrase va deficiency-an ultrarare metabolic decompensation syndrome presenting with hyperammonemia, lactic acidosis, ketonuria, and good clinical outcome.

索引：JIMD Reports,2021, 57(1): 9-14.

摘要：The combination of neonatal hyperammonemia, lactic acidosis, ketonuria, and hypoglycemia is pathognomonic for carbonic anhydrase VA (CA-VA) deficiency. We present two cases of this rare inborn error of metabolism. Both newborns with South Asian ancestry presented with a metabolic decompensation characterized by hyperammonemia, lactic acidosis and ketonuria; one also had hypoglycemia. Standard metabolic investigations (plasma amino acids, acylcarnitine profile, and urine organic acids) were not indicative of a specific organic aciduria or fatty acid oxidation defect but had some overlapping features with a urea cycle disorder (elevated glutamine, orotic acid, and low argi-nine). Hyperammonemia was treated initially with nitrogen scavenger therapy and carglumic acid. One patient required hemodialysis. Both have had a favorable long-term prognosis after their initial metabolic decompensation. Genetic testing confirmed the diagnosis of carbonic anhydrase VA (CA-VA) deficiency due to biallelic pathogenic variants in CA5A. These cases are in line with 15 cases previously described in the literature, making the phenotypic presentation pathognomonic for this ultrarare (potentially underdiagnosed) inborn error of metabolism with a good prognosis.

10.     题目：Onset of psychiatric signs and impaired neurocognitive domains in inherited metabolic disorders: A case series.

索引：JIMD Reports ,2021,58(1): 29-36.

摘要：Inherited metabolic disorders (IMDs) can present with psychiatric signs that vary widely from one disease to another. This picture is further complicated by the fact that these features occur at very different illness time points, which may further delay appropriate diagnosis and treatment. In this case series of 62 children and adolescents suffering from IMDs, we clustered psychiatric signs (on the basis of the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders classification) as well as impaired cognitive domains (on the basis of the Research Domain Criteriamatrix) according to their mean age of onset (5.7 +/- 4 years). We observed consistent patterns of occurrence across disorders. Externalizing symptoms, sleep problems, and cross-domain self-regulation deficits were found to precede the IMD diagnosis. Repetitive thoughts and behaviors as well as emotional dysregulation were found to occur around the disease onset. Finally, late-onset features included dissociative or eating disorders, together with impaired emotion knowledge. Clinicians should specifically look for the co-occurrence of age-specific atypical signs, such as treatment resistance or worsening with psychotropic medication in the earliest stages and symptom fluctuation, confusion, catatonia, or isolated visual hallucinations. We believe that the combined characterizations of psychiatric signs and impaired neurocognitive domains may enable the earliest detection of IMDs and the appropriate care of these particular manifestations. Key Points: Psychiatric signs are common in inherited metabolic disorders (IMDs) and may occur in the same age-range as other clinical manifestations. Three clusters of psychiatric signs and two clusters of neurocognitive domains can be defined according to their mean age of onset. Warning signs to be used in liaison psychiatry should include age-specific cognitive impairments.

11.     题目：Newborn screening for proximal urea cycle disorders: Current evidence supporting recommendations for newborn screening.

索引：Molecular Genetics & Metabolism ,2018,124(2): 109-113.

摘要：Current newborn screening (NBS) for urea cycle disorders (UCD) is incomplete as only distal UCDs are included in most NBS programs by measuring elevated amino acid concentrations. NBS for the proximal UCDs involves the detection in NBS spots of low citrulline values, a finding which is often overlooked because it is considered to be inadequate. We retrospectively analyzed NBS blood spots from known UCD patients comparing the utility of the Region 4 Stork (R4S) interpretive tools to conventional cutoff based interpretation. This study shows the utility of R4S tools in detecting all UCDs, and provides evidence to support the nomination to add proximal UCDs to the recommended uniform screening panel.

12.     题目：New ratio as a useful marker for early diagnosis of proximal urea cycle disorders.

索引：Clinica Chimica Acta,2021, 520(pp 154-159).

摘要：Background and aims: Proximal urea cycle disorders (PUCDs) are not included in most newborn screening programs due to the lack of adequate markers to monitor. Failure to alter citrulline and glutamine levels, the prognostic markers commonly used, can results in high false negative. Therefore, new biomarkers, prognostic of PUCDs, are strongly desirable.Materials and methods: We used tandem mass spectrometry to analyze blood spot from PUCDs patients during their follow up in our referral center focusing on glutamine to glutamate (Gln/Glu) ratio. We reanalyzed the same specimens of three patients after two months and the specimen of a new patient with suspicious of PUCD disorder.Results: Specimens of our patients shown a significant elevation of the ratio Gln/Glu compared to that of a healthy population (p < 0.05) as well as the specimens analyzed after two months, while the glutamine concentration dropped. New patient, showing high value of the ratio, was molecularly confirmed as PUCD patient. We further analyzed the blood spots from a neonatal population in order to fix a cut-off value and include it in a newborn screening panel.Conclusion: Our preliminary results suggest that the Gln/Glu ratio could be a very useful diagnostic marker, more stable over time than glutamine, which could improve the performance in early PUCDs identification.

13.     题目：Urea Cycle Disorders: A Neuroimaging Pattern Approach Using Diffusion and FLAIR MRI.

索引：Journal of Neuroimaging,2021, 31(1): 144-150.

摘要：Background and purpose: This study aimed to assess characteristic regions of MRI involvement utilizing diffusion weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) at urea cycle disorder (UCD) diagnosis to determine the possible association between initial MRI patterns within 10 days of the first hyperammonemia episode, serum ammonia levels, and severity of neurological outcome based on clinical follow-up of >30 days.Methods: Ten patients with UCDs (4 females; median age: 5.4 years, age range: 6 days-54 years) were included who underwent MRI during a first episode of hyperammonemia. The topographical distribution of the DWI and FLAIR abnormalities in the cerebral cortex, deep gray matter, white matter, posterior limb of internal capsule, cerebral peduncle, and cerebellum was evaluated. Possible correlations between the brain injury patterns on DWI/FLAIR images, serum ammonia levels, and severity of neurological outcome were investigated by a trend correlation.Results: The UCD cohort (n = 10) involved four ornithine transcarbamoylase deficiencies, four argininosuccinic aciduria, one carbomoylphosphate synthetase deficiency, and one citrullinemia type-1. The observed trend in the distribution of DWI abnormalities as the severity of neurological sequela outcome increased was with diffuse cerebral cortex or corpus striatum involvement. Patients with initial peak serum ammonia ≥450 µmol/L had a grade 2 to 4 outcome, and those with peak ammonia <450 µmol/L had a grade 0 or 1 outcome.Conclusions: The presence of more severe neurological outcome could be associated with diffuse cerebral cortex or corpus striatum involvement on DWI and high serum ammonia levels in patients with UCD.

14.     题目：Clinical and biochemical characteristics of patients with ornithine transcarbamylase deficiency.

索引：Clinical Biochemistry,2020, 84: 63-72.

摘要：BACKGROUND: Ornithine transcarbamylase deficiency (OTCD) is pleomorphic congenital hyperammonemia, in which the prognosis of the patient is determined both by genotype and environmental factors. This study investigated the clinical and biochemical characteristics of OTCD patients with different prognosis.METHOD: Of 35 OTCD patients, six males deceased at the first disease-onset, 17 males survived and had controllable ammonia levels after treatment, and 12 females survived through the first disease-onset but had intractable hyperammonemia and high mortality. Fasting blood samples from patients collected at three disease stages were used for the analysis of amino acid (AA) profile, acylcarnitine profile, and micronutrients. Differences in profiles between patients and healthy controls and within patient groups were studied.RESULTS: All OTCD patients had accumulation of glutamine, homocitrulline, lysine, glutamate, cystathionine, and pipecolic acid, as well as deficiency of citrulline, tryptophan, threonine, and carnitine. For male non-survivors, most other AAs and long-chain acylcarnitines were elevated at disease onset, of which the levels of creatine, N-acetylaspartic acid, and homoarginine were remarkably high. Male survivors and female patients had most other AAs at low to normal levels. Compared with male survivors, female patients had much lower protein-intolerance, as indicated by significantly lower levels of protein consumption indicators, including essential AAs, 1-methylhistidine, acylcarnitines et al., but high levels of ammonia. Female patients still had significantly higher levels of citrulline, homocitrulline, and citrulline/arginine compared to male survivors.CONCLUSION: Unique profiles were observed in each group of OTCD patients, indicating specific physiological changes that happened to them.

15.     题目：Simultaneous quantification of 48 plasma amino acids by liquid chromatography-tandem mass spectrometry to investigate urea cycle disorders.

索引： Clinica Chimica Acta,2019, 495(pp 406-416).

摘要：Urea cycle disorders (UCD) are inborn errors of ammonia detoxification in which early diagnosis and treatment are critical to prevent metabolic emergencies. Unfortunately, the diagnosis was often and pronounced delayed. To improve diagnosis, we developed herein a liquid chromatography-tandem mass spectrometry method to investigate the disturbance of amino acid profile caused by UCD. The method enabled absolute quantification of 48 amino acids (AAs) within 20 min. Only 2.5 muL plasma was required for the analysis. The lower limits of quantification for most AAs were 0.01 mumol/L. Method accuracies ranged from 89.9% to 113.4%. The within- and between-run coefficients of variation were 0.8-7.7% and 2.6-14.5%, respectively. With this method, age-specific reference values were established for 42 AAs by analyzing 150 samples from normal controls, and patients with different subtypes of UCD were successfully distinguished. The data of patients revealed that UCD not only disturbed the metabolism of urea cycle AAs and induced accumulation of ammonia detoxification AAs, but also interfered the metabolism of some nervous system related AAs, such as pipecolic acid and N-acetylaspartic acid. This data may provide new insight into pathogenesis for UCD.

16.     题目：Severity-adjusted evaluation of newborn screening on the metabolic disease course in individuals with cytosolic urea cycle disorders.

索引：Molecular Genetics and Metabolism,2020, 131(4): 390-397.

摘要：Objective: The implementation of newborn screening (NBS) programs for citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) is subject to controversial debate. The aim of this study was to assess the impact of NBS on the metabolic disease course and clinical outcome of affected individuals.Methods: In 115 individuals with CTLN1 and ASA, we compared the severity of the initial hyperammonemic episode (HAE) and the frequency of (subsequent) HAEs with the mode of diagnosis. Based on a recently established functional disease prediction model, individuals were stratified according to their predicted severe or attenuated phenotype.Results: Individuals with predicted attenuated forms of CTLN1 and ASA were overrepresented in the NBS group, while those with a predicted severe phenotype were underrepresented compared to individuals identified after the manifestation of symptoms (SX). Identification by NBS was associated with reduced severity of the initial HAE both in individuals with predicted severe and attenuated phenotypes, while it was not associated with lower frequency of (subsequent) HAEs. Similar results were obtained when including some patients diagnosed presymptomatically (i.e. prenatal testing, and high-risk family screening) in this analysis.Conclusion: Since one of the major challenges of NBS outcome studies is the potential overrepresentation of individuals with predicted attenuated phenotypes in NBS cohorts, severity-adjusted evaluation of screened and unscreened individuals is important to avoid overestimation of the NBS effect. NBS enables the attenuation of the initial HAE but does not affect the frequency of subsequent metabolic decompensations in individuals with CTLN1 and ASA. Future long-term studies will need to evaluate the clinical impact of this finding, especially with regard to mortality, as well as cognitive outcome and quality of life of survivors.

17.     题目：Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: Selective screening vs. expanded newborn screening.

索引： Molecular Genetics and Metabolism Reports,2018, 16(pp 5-10).

摘要：Background: Expanded newborn screening (ENBS) utilizing tandem mass spectrometry (MS/MS) for inborn metabolic diseases (IMDs), such as organic acidemias (OAs), fatty acid oxidation disorders, (FAODs), and amino acid disorders (AAs), is increasingly popular but has not yet been introduced in many Asian countries. This study aimed to determine the incidence rates of OAs, FAODs, and AAs in Asian countries and Germany using selective screening and ENBS records.Materials and methods: Selective screening for IMDs using gas chromatography-mass spectrometry and MS/MS was performed among patients suspected to be afflicted in Asian countries (including Japan, Vietnam, China, and India) between 2000 and 2015, and the results from different countries were compared. Similarly, ENBS results from Japan, South Korea, Taiwan, and Germany were compared. Additionally, the results of selective screening and ENBS in Japan were compared.Results: Among 39,270 patients who underwent selective screening, IMDs were detected in 1170. Methylmalonic acidemia was frequently identified in several countries, including Japan (81/377 diagnosed IMDs), China (94/216 IMDs), and India (72/293 IMDs). In Vietnam, however, β-ketothiolase deficiency was particularly frequent (33/250 IMDs). ENBS yielded differences in overall IMD rates by country: 1:8557 in Japan, 1:7030 in Taiwan, 1:13,205 in South Korea, and 1:2200 in Germany. Frequently discovered diseases included propionic acidemia (PPA) and phenylketonuria (PKU) in Japan, 3-methylcrotonyl-CoA carboxylase deficiency (MCCD) and PKU in Taiwan, MCCD and citrullinemia type I in South Korea, and PKU and medium-chain acyl-CoA dehydrogenase deficiency in Germany. Furthermore, in Japan, selective screening and ENBS yielded respective PPA frequencies of 14.7% and 49.4% among all organic acidemias.Conclusion: The incidence rates of IMDs vary by country. Moreover, the disease spectra of IMDs detected via selective screening differ from those detected via ENBS.

18.     题目：The role of orotic acid measurement in routine newborn screening for urea cycle disorders."

索引：Journal of Inherited Metabolic Disease,2021,44(3): 606-617.

摘要：Urea cycle disorders (UCDs), including OTC deficiency (OTCD), are life-threatening diseases with a broad clinical spectrum. Early diagnosis and initiation of treatment based on a newborn screening (NBS) test for OTCD with high specificity and sensitivity may contribute to reduction of the significant complications and high mortality. The efficacy of incorporating orotic acid determination into routine NBS was evaluated. Combined measurement of orotic acid and citrulline in archived dried blood spots from newborns with urea cycle disorders and normal controls was used to develop an algorithm for routine NBS for OTCD in Israel. Clinical information and genetic confirmation results were obtained from the follow-up care providers. About 1147986 newborns underwent routine NBS including orotic acid determination, 25 of whom were ultimately diagnosed with a UCD. Of 11 newborns with OTCD, orotate was elevated in seven but normal in two males with early-onset and two males with late-onset disease. Orotate was also elevated in archived dried blood spots of all seven retrospectively tested historical OTCD patients, only three of whom had originally been identified by NBS with low citrulline and elevated glutamine. Among the other UCDs emerge, three CPS1D cases and additional three retrospective CPS1D cases otherwise reported as a very rare condition. Combined levels of orotic acid and citrulline in routine NBS can enhance the detection of UCD, especially increasing the screening sensitivity for OTCD and differentiate it from CPS1D. Our data and the negligible extra cost for orotic acid determination might contribute to the discussion on screening for proximal UCDs in routine NBS.

19.     题目：Clinical utility of brain MRS imaging of patients with adult-onset non-cirrhotic hyperammonemia.

索引：Molecular Genetics and Metabolism Reports 27 (no pagination), 2021,Date of Publication: June 2021.

摘要：Adult-onset non-cirrhotic hyperammonemia (NCH) is a rare, but often fatal condition that can result in both reversible and irreversible neurological defects. Here we present five cases of adult-onset non-cirrhotic hyperammonemia wherein brain magnetic resonance spectroscopy (MRS) scans for cerebral glutamine (Gln) and myo-inositol (mI) levels helped guide clinical management. Specifically, we demonstrate that when combined with traditional brain magnetic resonance imaging (MRI) scans, cerebral Gln and mI MRS can help disentangle the reversible from irreversible neurological defects associated with hyperammonemic crisis. Specifically, we demonstrate that whereas an elevated brain MRS Gln level is associated with reversible neurological defects, markedly low mI levels are associated with a risk for irreversible neurological defects such as central pontine myelinolysis. Overall, our findings indicate the utility of brain MRS in guiding clinical care and prognosis in patients with adult-onset non-cirrhotic hyperammonemia.

20.     题目：High blood pressure, a red flag for the neonatal manifestation of urea cycle disorders.

索引： Orphanet Journal of Rare Diseases 14(1) (no pagination), 2019,Date of Publication: 08 Apr 2019.

摘要：Background: Neonatal manifestation of life-threatening hyperammonemic encephalopathy in urea cycle disorders (UCD) is often misdiagnosed as neonatal sepsis, resulting in significantly delayed start of specific treatment and poor outcome. The major aim of this study was to identify specific initial symptoms or signs to clinically distinguish hyperammonemic encephalopathy in neonates from neonatal sepsis in order to identify affected individuals with UCD and to start metabolic therapy without delay. Furthermore, we evaluated the impact of diagnostic delay, peak plasma ammonium (NH4+) concentration, mode of emergency treatment and transfer to a tertiary referral center on the outcome.Methods: Detailed information of 17 patients (born between 1994 and 2012) with confirmed diagnosis of UCD and neonatal hyperammonemic encephalopathy were collected from the original medical records.Results: The initially suspected diagnosis was neonatal sepsis in all patients, but was not confirmed in any of them. Unlike neonatal sepsis and not previously reported blood pressure increased above the 95th percentile in 13 (81%) of UCD patients before emergency treatment was started. Respiratory alkalosis was found in 11 (65%) of UCD patients, and in 14 (81%) plasma NH4+concentrations further increased despite initiation of metabolic therapy.Conclusion: Detection of high blood pressure could be a valuable parameter for distinguishing neonatal sepsis from neonatal manifestation of UCD. Since high blood pressure is not typical for neonatal sepsis, other reasons such as encephalopathy and especially hyperammonemic encephalopathy (caused by e.g. UCD) should be searched for immediately. However, our result that the majority of newborns with UCD initially present with high blood pressure has to be evaluated in larger patient cohorts.

21.     题目：Differences in faecal microbiome composition between adult patients with UCD and PKU and healthy control subjects.

索引：Molecular Genetics and Metabolism Reports 29 (no pagination), 2021,Date of Publication: December 2021.

摘要：Urea cycle disorders (UCDs) are a group of rare inherited metabolic diseases causing hyperammonemic encephalopathy. Despite intensive dietary and pharmacological therapy, outcome is poor in a subset of UCD patients. Reducing ammonia production by changing faecal microbiome in UCD is an attractive treatment approach. We compared faecal microbiome composition of 10 UCD patients, 10 healthy control subjects and 10 phenylketonuria (PKU) patients. PKU patients on a low protein diet were included to differentiate between the effect of a low protein diet and the UCD itself on microbial composition. Participants were asked to collect a faecal sample and to fill out a 24 h dietary journal. DNA was extracted from faecal material, taxonomy was assigned and microbiome data was analyzed, with a focus on microbiota involved in ammonia metabolism. In this study we show an altered faecal microbiome in UCD patients, different from both PKU and healthy controls. UCD patients on dietary and pharmacological treatment had a less diverse faecal microbiome, and the faecal microbiome of PKU patients on a protein restricted diet with amino acid supplementation showed reduced richness compared to healthy adults without a specific diet. The differences in the microbiome composition of UCD patients compared to healthy controls were in part related to lactulose use. Other genomic process encodings involved in ammonia metabolism, did not seem to differ. Since manipulation of the microbiome is possible, this could be a potential treatment modality. We propose as a first next step, to study the impact of these faecal microbiome alterations on metabolic stability. Take home message: The faecal microbiome of UCD patients was less diverse compared to PKU patients and even more compared to healthy controls.

22.     题目：Biochemical markers and neuropsychological functioning in distal urea cycle disorders.

索引：Journal of Inherited Metabolic Disease,2018, 41(4): 657-667.

摘要：Urea cycle disorders often present as devastating metabolic conditions, resulting in high mortality and significant neuropsychological damage, despite treatment. The Urea Cycle Disorders Longitudinal Study is a natural history study that collects data from regular clinical follow-up and neuropsychological testing. This report examines links between biochemical markers (ammonia, glutamine, arginine, citrulline) and primary neuropsychological endpoints in three distal disorders, argininosuccinic acid synthetase deficiency (ASD or citrullinemia type I), argininosuccinic acid lyase deficiency (ASA or ALD), and arginase deficiency (ARGD). Laboratory results and test scores from neuropsychological evaluations were assessed in 145 study participants, ages 3 years and older, with ASD (n = 64), ASA (n = 65) and ARGD (n = 16). Mean full scale IQ was below the population mean of 100 +/- 15 for all groups: (ASD = 79 +/- 24; ASA = 71 +/- 21; ARGD = 65 +/- 19). The greatest deficits were noted in visual performance and motor skills for all groups. While ammonia levels remain prominent as prognostic biomarkers, other biomarkers may be equally valuable as correlates of neuropsychological functioning. Cumulative exposure to the biomarkers included in the study proved to be highly sensitive indicators of neuropsychological outcomes, even when below the cut-off levels generally considered toxic. Blood levels of biomarkers obtained on the day of neuropsychological evaluations were not correlated with measures of functioning for any disorder in any domain. The importance of cumulative exposure supports early identification and confirms the need for well-controlled management of all biochemical abnormalities (and not just ammonia) that occur in urea cycle disorders.

23.     题目：The utility of EEG monitoring in neonates with hyperammonemia due to inborn errors of metabolism.

索引：Molecular Genetics and Metabolism,2018, 125(3): 235-240.

摘要：Background: Continuous EEG studies demonstrate that neonates with seizures due to cerebral pathology, such as hypoxia ischemia, exhibit predominantly electrographic seizures (i.e. those only detected with EEG because they lack clinical features). Previous small case series demonstrate EEG changes and seizures during hyperammonemia associated with inborn errors of metabolism (IEM) but there are no reports utilizing continuous EEG in these conditions.Objective: To characterize seizures and evaluate the utility of continuous EEG recording during hyperammonemia due to inborn errors of metabolism.Methods: We retrospectively reviewed medical records and EEG tracings of neonates who presented with hyperammonemia due to inborn errors of metabolism who had continuous EEG and full medical records available for review, including follow up.Results: Eight neonates with hyperammonemia were studied, 7 had urea cycle defects: Argininosuccinate lyase deficiency [3], (ornithine transcarbamylase deficiency [3], carbomyl phosphate synthase deficiency [1] and one had an organic acidemia: Methylmalonic acidemia [1]. Most common presentations were lethargy and poor feeding at 12-72 h of life. The highest blood ammonia level was 874 μmol/L (median); range 823-1647 μmol/L (normal value <50 μmol/L in term neonates). Seven were treated with hemodialysis in addition to nitrogen scavengers. Seven neonates had seizures; six had only electrographic seizures. Seizures initially occurred within 24-36 h of clinical presentation, sometimes with normal ammonia and glutamine levels. Neonates with seizures all lacked state changes on EEG. Inter burst interval duration correlated with degree of hyperammonemia. Two cases with normal plasma ammonia but increasing interburst interval duration were proven to have stroke by MRI.Conclusions: Seizures occur frequently in neonates with hyperammonemia; most can be detected only with continuous EEG. Seizures may occur when ammonia and glutamine levels are normal. Interburst interval duration is associated with ammonia levels or cerebral dysfunction from other brain pathology. Continuous EEG can be a useful tool for managing infants with hyperammonemia and may be essential for seizure management especially for infants in deep metabolic coma.

24.     题目：Two Novel Heterozygous MCCC1 Mutations in a Neonate with Asymptomatic 3-methylcrotonyl-coenzyme A Carboxylase Deficiency.

索引： Indian Pediatrics ,2018,55(6)：528.

25.     题目：The Application of Next-Generation Sequencing (NGS) in Neonatal-Onset Urea Cycle Disorders (UCDs): Clinical Course, Metabolomic Profiling, and Genetic Findings in Nine Chinese Hyperammonemia Patients.

索引： BioMed Research International 2020 (no pagination), 2020,Date of Publication: 2020.

摘要：During Jan. 2016-Dec. 2019, nine Chinese patients from eight unrelated families were diagnosed with neonatal-onset UCDs by targeted panel sequencing or whole-exome sequencing (WES). Their clinical manifestations, biochemical features, 180-day-age outcomes, and molecular genetic characteristics were reviewed retrospectively. NGS-based tests revealed 7 patients diagnosed with ornithine transcarbamylase deficiency (OTCD) and 2 with carbamoylphosphate synthetase I deficiency (CPS1D). The spectrum of the clinical presentation of nine affected individuals progressed from unspecific symptoms like poor feeding to somnolence, coma, and death. All patients presented with an acute hyperammonemia. The most robust metabolic pattern in OTCD was hyperglutaminemic hyperammonemia with high concentration of urine orotic acid, and it was reported in six patients. Of ten variants found on the OTC gene and CPS1 gene, 3 were novel: (c.176T>C (p.L59P)) in the OTC gene, c.2938G>A (p.G980S) and c.3734T>A (p.L1245H) in the CPS1 gene. There was a high mortality rate of 77.78% (7/9) for all the defects combined. An OTC-deficient male and a CPS1-deficient female survived from episodes of hyperammonemia. Although prompt recognition of UCD and the use of alternative pathway therapy in addition to provision of appropriate nutrition and dialysis improved survival, the overall outcomes for the neonatal-onset type are poor in China.