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Research Publications

Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database. Sen K, Izem R, Long Y, Jiang J, Konczal LL, McCarter RJ. Mol Genet Genomic Med. 2024 Apr;12(4):e2443. doi: 10.1002/mgg3.2443. PMID: 38634223; PMCID: PMC11024633.

Ornithine transcarbamylase deficiency (OTCD) is a type of urea cycle disorder characterized by hyperammonemia (high blood ammonia levels) due to deficiency or absence of an enzyme needed to convert nitrogen from protein into urea (a waste product). Because OTCD is caused by an X-linked mutation in the OTC gene, the majority of patients with severe presentation of OTC deficiency are male, as they have only one X chromosome. Although 80% of females with OTCD are typically thought to remain asymptomatic, not much is known about their clinical characteristics and long-term health vulnerabilities. 

In this study, researchers explored the factors that might predict development of defined complications and serious illness in apparent asymptomatic females with OTCD. The team reviewed data from 302 females enrolled in the Urea Cycle Disorders Consortium (UCDC) longitudinal natural history study. Researchers also performed several types of neuroimaging studies in a female patient with OTCD.

Results show that these patients can experience neuropsychiatric and behavioral symptoms as well as an increased risk of hyperammonemia later in life, demonstrating that asymptomatic females with OTCD are not always asymptomatic. Authors note that these findings can aid in the development of a risk calculator and improve guidelines for management of these patients, paving the way for potential new therapies.

Impact of supplementation with L-citrulline/arginine after liver transplantation in individuals with Urea Cycle Disorders. Posset R, Garbade SF, Gleich F, Nagamani SCS, Gropman AL, Epp F, Ramdhouni N, Druck AC, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) consortia study group. Mol Genet Metab. 2024 Mar;141(3):108112. doi: 10.1016/j.ymgme.2023.108112. Epub 2023 Dec 10. PMID: 38301530.

Urea cycle disorders (UCDs) are genetic disorders that result in a deficiency of one of the six enzymes in the urea cycle, causing hyperammonemia (high blood ammonia levels). When medical management is not enough to prevent hyperammonemia, patients with UCDs may undergo liver transplantation. Both before and after transplant, these patients often receive L-citrulline or L-arginine supplements to help their bodies eliminate ammonia. However, not much is known about the impact of long-term supplementation.

In this pilot study, researchers investigated the effects of long-term L-citrulline or L-arginine supplementation in patients with UCDs who have undergone liver transplantation. The team used data collected from longitudinal observational studies to compare outcomes of 16 patients who received these supplements long-term with 36 patients who were not supplemented over the course of 4 or 5 years after transplant.

Results suggest that although supplementation with L-citrulline or L-arginine is often continued after transplant, in this pilot study, such supplementation was not associated with health-related outcomes or biochemical responses. Authors note that analyzing larger samples over longer observation periods will provide more insight into the usefulness of long-term supplementation.

Barriers to a successful healthcare transition for individuals with urea cycle disorders. Ladha FA, Le Mons C, Craigen WJ, Magoulas PL, Marom R, Lewis AM. Mol Genet Metab. 2023 Jul;139(3):107609. doi: 10.1016/j.ymgme.2023.107609. Epub 2023 May 15.

Delayed skeletal development and IGF-1 deficiency in a mouse model of lysinuric protein intolerance. Stroup BM, Li X, Ho S, Zhouyao H, Chen Y, Ani S, Dawson B, Jin Z, Marom R, Jiang MM, Lorenzo I, Rosen D, Lanza D, Aceves N, Koh S, Seavitt JR, Heaney JD, Lee B, Burrage LC. Dis Model Mech. 2023 Aug 1;16(8):dmm050118. doi: 10.1242/dmm.050118. Epub 2023 Aug 17.

Health-related quality of life in a systematically assessed cohort of children and adults with urea cycle disorders. Murali CN, Barber JR, McCarter R, Zhang A, Gallant N, Simpson K, Dorrani N, Wilkening GN, Hays RD, Lichter-Konecki U; Members of the Urea Cycle Disorders Consortium; Burrage LC, Nagamani SCS. Mol Genet Metab. 2023 Sep 8;140(3):107696. doi: 10.1016/j.ymgme.2023.107696. Epub ahead of print. PMID: 37690181

Urea cycle disorders (UCDs) are a group of inherited, metabolic disorders characterized by hyperammonemia (high blood ammonia levels). Accumulation of ammonia is toxic to the nervous system, resulting in neurological symptoms that can impact health-related quality of life (HRQoL). However, only a few studies have systematically investigated the impact of UCDs on HRQoL.

In this study, researchers assessed HRQoL in a large cohort of children and adults with UCDs. The team reviewed HRQoL and clinical data from a Urea Cycle Disorders Consortium longitudinal study; compared to healthy individuals and those with PKU and diabetes; and assessed relationships between HRQoL, UCD diagnosis, and disease severity.

Results show that individuals with UCDs have worse HRQoL compared to healthy individuals and those with PKU and diabetes. Authors state that future work should focus on the impact of liver transplantation and other clinical variables on HRQoL in UCDs.

Monitoring the treatment of urea cycle disorders using phenylbutyrate metabolite analyses: Still many lessons to learn. Glinton KE, Minard CG, Liu N, Sun Q, Elsea SH, Burrage LC, Nagamani SCS. Mol Genet Metab. 2023 Nov;140(3):107699. doi: 10.1016/j.ymgme.2023.107699. Epub 2023 Sep 11.

Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders. Posset R, Garbade SF, Gleich F, Scharre S, Okun JG, Gropman AL, Nagamani SCS, Druck AC, Epp F, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC); European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. Genet Med. 2023 Dec 3;26(4):101039. doi: 10.1016/j.gim.2023.101039. Epub ahead of print. PMID: 38054409.

Urea cycle disorders (UCDs) are a group of inherited, metabolic disorders characterized by hyperammonemia (high blood ammonia levels). Patients with UCD may undergo liver transplantation when medical management is not enough to prevent hyperammonemia. However, not much is known about how the effects of transplant compare to medical management alone.

In this study, researchers classified patients into “severe” and “attenuated” categories based on genetic information and a novel enzyme activity test. Then, using data collected from longitudinal observational studies, they compared the health-related outcomes in patients who underwent liver transplantation vs medical management. 

Results show that liver transplantation led to greater metabolic stability without the need for protein restriction or nitrogen-scavenging therapy. However, while transplantation led to more favorable growth outcomes, it was not associated with improved neurocognitive outcomes compared to long-term medical management.

The challenge of understanding and predicting phenotypic diversity in urea cycle disorders. Posset R, Zielonka M, Gleich F, Garbade SF, Hoffmann GF, Kölker S; Urea Cycle Disorders Consortium (UCDC) and European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. J Inherit Metab Dis. 2023 Nov;46(6):1007-1016. doi: 10.1002/jimd.12678. Epub 2023 Oct 10.

Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency. Scharre S, Posset R, Garbade SF, Gleich F, Seidl MJ, Druck AC, Okun JG, Gropman AL, Nagamani SCS, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. Ann Clin Transl Neurol. 2022 Oct 10. doi: 10.1002/acn3.51668. Epub ahead of print. PMID: 36217298.

Ornithine transcarbamylase deficiency (OTC-D) is an X-linked disorder and the most common type of urea cycle disorder. Patients with OTC-D can present with a variable spectrum of disease severity, ranging from no symptoms to lethal hyperammonemia (high blood ammonia levels). Therefore, predicting disease course at an early stage is important to personalize therapies for individual patients, which can include medical treatment or liver transplantation. In this study, researchers developed a new cell-based system to assess the residual enzyme activity associated with various disease-causing genetic changes in the OTC gene. Using this system, they were able to correlate residual enzymatic OTC activities with clinical and biochemical outcome parameters of 119 male individuals with OTC-D. Results show that residual enzymatic OTC activity can distinguish individuals with a severe form of OTC-D from those with milder forms of the disorder. As a reliable predictor of disease severity in OTC-D, this classification system could help guide therapeutic strategies and counseling of patients and parents.

Review of Applications of Near-Infrared Spectroscopy in Two Rare Disorders with Executive and Neurological Dysfunction: UCD and PKU. Khaksari K, Chen WL, Gropman AL. Genes (Basel). 2022 Sep 21;13(10):1690. doi: 10.3390/genes13101690. PMID: 36292574; PMCID: PMC9602148.

Urea cycle disorders (UCD) and phenylketonuria (PKU) are two types of genetic, metabolic disorders characterized by neurological symptoms. As with many rare diseases, small population size can make these disorders challenging to study. Tools such as functional neuroimaging are developed to help generate biomarkers, collect baseline data, and measure treatment effects in patients with neurological disorders. However, the cost and infrastructure requirements of these tools have limited their availability. To address this challenge, researchers and clinicians are developing new tools that are non-invasive, portable, and inexpensive. In this review article, researchers discuss the use of functional near-infrared spectroscopy (fNIRS)—a non-invasive, portable tool that uses blood oxygenation to view the brain—in patients with UCD and PKU. Authors consider the ability of fNIRS to obtain biomarkers for screening and monitoring these diseases.

ASL expression in ALDH1A1+ neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype. Lerner S, Eilam R, Adler L, Baruteau J, Kreiser T, Tsoory M, Brandis A, Mehlman T, Ryten M, Botia JA, Ruiz SG, Garcia AC, Dionisi-Vici C, Ranucci G, Spada M, Mazkereth R, McCarter R, Izem R, Balmat TJ, Richesson R; Members of the UCDC, Gazit E, Nagamani SCS, Erez A. Hum Genet. 2021 Oct;140(10):1471-1485. doi: 10.1007/s00439-021-02345-5. Epub 2021 Aug 21.

In the liver, the enzymes argininosuccinate lyase (ASL) and argininosuccinate synthase 1 (ASS1) are required to convert waste-nitrogen to urea. Loss of activity for either enzyme causes argininosuccinate lyase deficiency and citrullinemia type 1, respectively. These two disorders are a subset of the classical inborn errors of metabolism called urea cycle disorders (UCD), characterized by episodes of hyperammonemia. ASL deficiency can also result in impaired nitric oxide (NO) synthesis, decreased tyrosine hydroxylase (TH) activity, and low dopamine and norepinephrine levels in the neuronal cells. Both dopamine and norepinephrine are important neurotransmitters, and their deficiency has been associated with neurodegenerative disorders, including Parkinson's Disease. In this study, researchers used a mouse model with loss of ASL in catecholamine neurons to test the hypothesis that decreased activity of ASL and TH would contribute to neurodegeneration. They found that neuronal loss of ASL results in catecholamine deficiency, in accumulation and formation of tyrosine aggregates, in elevation of α-synuclein, and phenotypically in motor and cognitive deficits. Study authors say their data point to a potential metabolic link between accumulations of tyrosine and seeding of pathological aggregates in neurons as initiators for the pathological processes involved in neurodegeneration. They suggest that regulating NO levels may be beneficial for the treatment of catecholamine-related neurodegenerative disorders.

Biomarkers for liver disease in urea cycle disorders. Nagamani SCS, Ali S, Izem R, Schady D, Masand P, Shneider BL, Leung DH, Burrage LC. Mol Genet Metab. 2021 Apr 8:S1096-7192(21)00685-5. doi: 10.1016/j.ymgme.2021.04.001. Online ahead of print.

Clinical utility of brain MRS imaging of patients with adult-onset non-cirrhotic hyperammonemia. Stergachis AB, Krier JB, Merugumala SK, Berry GT, Lin AP. Mol Genet Metab Rep. 2021 Mar 13;27:100742. doi: 10.1016/j.ymgmr.2021.100742. eCollection 2021 Jun.

Comparison of Untargeted Metabolomic Profiling vs Traditional Metabolic Screening to Identify Inborn Errors of Metabolism. Liu N, Xiao J, Gijavanekar C, Pappan KL, Glinton KE, Shayota BJ, Kennedy AD, Sun Q, Sutton VR, Elsea SH. JAMA Netw Open. 2021 Jul 1;4(7):e2114155. doi: 10.1001/jamanetworkopen.2021.14155.

Inborn errors of metabolism (IEMs) are rare genetic disorders in which the body cannot properly turn food into energy. Newborn screening (NBS) has improved diagnosis of these diseases, but gaps remain as many of these rare diseases are not included on NBS panels. In this study, researchers evaluated the usefulness of untargeted metabolomics as a primary screening tool, comparing the diagnostic rate of clinical metabolomics to traditional newborn screening. They found that untargeted metabolomics improved the diagnostic rate for IEMs six-fold when compared to the traditional NBS approach. The metabolomics approach also identified a broader spectrum of IEMs. Authors say these data support the use of clinical untargeted metabolomics in screening for IEMs and suggest that broader screening approaches should be considered to help diagnose these rare diseases.

Expanding Role of Proton Magnetic Resonance Spectroscopy: Timely Diagnosis and Treatment Initiation in Partial Ornithine Transcarbamylase Deficiency. Sen K, Castillo Pinto C, Gropman AL. J Pediatr Genet. 2021 Mar;10(1):77-80. doi: 10.1055/s-0040-1709670. Epub 2020 Apr 23.

Fifteen years of urea cycle disorders brain research: Looking back, looking forward. Sen K, Whitehead M, Castillo Pinto C, Caldovic L, Gropman A. Anal Biochem. 2022 Jan 1;636:114343. doi: 10.1016/j.ab.2021.114343. Epub 2021 Oct 9. PMID: 34637785; PMCID: PMC8671367.

This new review paper highlights the evolving knowledge about the impact of urea cycle disorders (UCD) and hyperammonemia (HA) in particular on neurological injury and recovery. It discusses the use of electroencephalography (EEG) and magnetic resonance imaging (MRI) to study and evaluate prognostic factors for risk and recovery. It recognizes the work of others and discusses the UCDC's prior work and future research priorities, as well as lessons learned over 15 years of neuroimaging research. Key learnings include the identification of the insular cortex as the area most vulnerable to hyperammonemia in UCD. Elevated glutamine and decreased myoinosital have been identified as key brain biomarkers on proton magnetic resonance spectroscopy (MRS), with decreased choline seen over time in patients with repeat HA episodes. Slow recovery of brain glutamine after recovery from hyperammonemia is common. Researchers have found that 1H-MRS, a non-invasive technique that enables the detection, identification, and quantification of biochemical compounds or metabolites in the brain tissue, is most sensitive for proximal UCD and is often abnormal with elevated glutamine, before routine T1 and T2 sequences on MRI show abnormalities. In addition, our work demonstrates that more than one-third of female carriers of OTCD have the biochemical phenotype of UCD on MRS including mildly elevated glutamine and lower than normal myoinositol. 1H-MRS should be added to the clinical routine in patients with known and suspected metabolic conditions.

Randomized and non-randomized designs for causal inference with longitudinal data in rare disorders. Izem R, McCarter R. Orphanet J Rare Dis. 2021 Nov 23;16(1):491. doi: 10.1186/s13023-021-02124-5. PMID: 34814939; PMCID: PMC8609847.

Sound study design and causal inference methods are essential to demonstrate the therapeutic efficacy, safety, and effectiveness of new therapies. In the rare diseases setting, the small patient population size, genotypic and phenotypic diversity, and the complexity and incomplete understanding of the disorder's progression challenge the use of typical parallel control designs. This paper reviews longitudinal designs and draws the parallel between some new and existing randomized studies in rare diseases and their less well-known controlled observational study designs. Authors provide examples of analyses in multiple rare disorders, including urea cycle disorder and cystic fibrosis.

Review of Multi-Modal Imaging in Urea Cycle Disorders: The Old, the New, the Borrowed, and the Blue. Sen K, Anderson AA, Whitehead MT, Gropman AL. Front Neurol. 2021 Apr 28;12:632307. doi: 10.3389/fneur.2021.632307. eCollection 2021.

The Application of Neurodiagnostic Studies to Inform the Acute Management of a Newborn Presenting With Sarbamoyl Shosphate Synthetase 1 Deficiency. McGowan M, Ferreira C, Whitehead M, Basu SK, Chang T, Gropman A. Child Neurol Open. 2021 Jan 22;8:2329048X20985179. doi: 10.1177/2329048X20985179. eCollection 2021 Jan-Dec.

Chronic liver disease and impaired hepatic glycogen metabolism in argininosuccinate lyase deficiency. Burrage LC, Madan S, Li X, Ali S, Mohammad M, Stroup BM, Jiang MM, Cela R, Bertin T, Jin Z, Dai J, Guffey D, Finegold M; Members of the Urea Cycle Disorders Consortium (UCDC), Nagamani S, Minard CG, Marini J, Masand P, Schady D, Shneider BL, Leung DH, Bali D, Lee B. JCI Insight. 2020 Feb 27;5(4):e132342. doi: 10.1172/jci.insight.132342.

In this study, researchers reviewed participant data from the Urea Cycle Disorders Consortium’s (UCDC) Longitudinal Study that included all types of UCD. The data suggested that individuals with argininosuccinate lyase deficiency (ASLD) and arginase deficiency had a higher prevalence of liver injury as compared to other types of UCD. Researchers assessed liver disease in individuals with ASLD and a laboratory mouse model of ASLD. Around 37% individuals with ASLD had increased ALT levels. Some of the ASLD participants were noted to have increased liver stiffness but normal ALT and AST levels. The results showed that a quarter of the participants with normal ALT levels had abnormal liver imaging or testing. The ASLD study mice also developed chronic liver damage. These mice had excessive hepatic glycogen, liver enlargement, and increased ALT and AST levels. Hepatic glycogen accumulation has also been found in other types of UCD. More research is needed to identify the role of hepatic glycogen in UCD, as it is unknown whether it leads to, is the cause of, or is at all connected to damage in the liver. This study shows the need to identify additional biomarkers of liver damage in UCD.

Developing interactions with industry in rare diseases: lessons learned and continuing challenges. Berry SA, Coughlin CR 2nd, McCandless S, McCarter R, Seminara J, Yudkoff M, LeMons C. Genet Med. 2020 Jan;22(1):219-226. doi: 10.1038/s41436-019-0616-9. Epub 2019 Jul 24.

The NIH established the Rare Diseases Clinical Research Network to address the unique challenges of performing research on rare diseases. The UCDC was one of the original ten consortia established. Based in part on financial incentives associated with the Orphan Drug Act of 1983 (a United States law that helped catalyze the development of drugs for rare diseases), biopharmaceutical and investment entities have an intense interest in engaging with rare disease research consortia like the UCDC, which have compiled potentially valuable longitudinal data characterizing outcomes in a relatively large number of affected individuals. Natural history data from the longitudinal study are invaluable not only for the many exploratory studies conducted by the UCDC, but also to industry partners seeking to develop new therapeutics to improve the lives of UCD patients and ultimately a cure. This publication discusses the ways in which the UCDC navigates industry relationships in the pursuit of developing therapeutics for UCD patients. For example, the UCDC has developed a method for evaluating partnerships with private entities, established an Industry Relations Committee in 2015 to develop guiding principles, a policy and procedures for interacting with industry (including protection of data privacy), and managing investigator conflict of interest. By building a framework for industry partnerships that guides us in resolving inevitable challenges, the UCDC can pursue novel and promising collaborations that can lead to breakthroughs in treatment for patients.

Evaluation of neurocognitive function of prefrontal cortex in ornithine transcarbamylase deficiency. Anderson A, Gropman A, Le Mons C, Stratakis C, Gandjbakhche A. Mol Genet Metab. 2020 Mar;129(3):207-212. doi: 10.1016/j.ymgme.2019.12.014. Epub 2020 Jan 10. PMID: 31952925. Full Text.

From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria. Zielonka M, Garbade SF, Gleich F, Okun JG, Nagamani SCS, Gropman AL, Hoffmann GF, Kölker S, Posset R; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. Hum Mutat. 2020 May;41(5):946-960. doi: 10.1002/humu.23983. Epub 2020 Jan 30.

Argininosuccinic aciduria (ASA), caused by a deficiency in argininosuccinate lyase (ASL), is one of the more common urea cycle disorder subtypes. ASA has a wide range of symptoms ranging from mild disease to individuals with significant neurocognitive deficiencies. In this study, researchers analyzed previously collected patient data and correlated these with a new method of enzymatic testing for ASL to determine if the activity level of ASL was a reliable predictor of disease severity. The data was collected from the Longitudinal Study of UCD conducted by the Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD). The results showed that individuals with ASA with 8% or less ASL activity had higher initial ammonia levels and more frequent hyperammonemic episodes per year, and those with 8.7% or less ASL activity had increased liver damage. Overall, older ASL patients performed worse than younger ASL patients, which points to the possibility of chronic cognitive deterioration. The difference was more pronounced for those with ASL activity below 24.3%, suggesting additional underlying factors that affect cognition below a certain level of ASL activity. Based on the outcomes of this and previous studies, there is a possibility that ASL activity levels could help caregivers predict disease severity in ASA patients and inform the development of more effective, individualized treatments.

Hemodynamics of Prefrontal Cortex in Ornithine Transcarbamylase Deficiency: A Twin Case Study. Anderson AA, Gropman A, Le Mons C, Stratakis CA, Gandjbakhche AH. Front Neurol. 2020 Aug 14;11:809. doi: 10.3389/fneur.2020.00809. PMID: 32922350; PMCID: PMC7456944.

Late Onset Ornithine Transcarbamylase Deficiency Triggered by an Acute Increase in Protein Intake: A Review of 10 Cases Reported in the Literature. Barkovich E, Gropman AL. Case Rep Genet. 2020 Apr 25;2020:7024735. doi: 10.1155/2020/7024735. PMID: 32373372; PMCID: PMC7197010. 

Long-term effects of medical management on growth and weight in individuals with urea cycle disorders. Posset R, Garbade SF, Gleich F, Gropman AL, de Lonlay P, Hoffmann GF, Garcia-Cazorla A, Nagamani SCS, Baumgartner MR, Schulze A, Dobbelaere D, Yudkoff M, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC); European registry and network for Intoxication type Metabolic Diseases (E-IMD). Sci Rep. 2020 Jul 20;10(1):11948. doi: 10.1038/s41598-020-67496-3.

Multimodal imaging in urea cycle-related neurological disease - What can imaging after hyperammonemia teach us. Sen K, Whitehead MT, Gropman AL. Transl Sci Rare Dis. 2020 Aug 3;5(1-2):87-95. doi: 10.3233/TRD-200048.

Novel imaging technologies for genetic diagnoses in the inborn errors of metabolism. Gropman AL, Anderson A. J Transl Genet Genom. 2020;4:429-445. doi: 10.20517/jtgg.2020.09. Epub 2020 Nov 13.

Phenotypic expansion of Bosch-Boonstra-Schaaf optic atrophy syndrome and further evidence for genotype-phenotype correlations. Rech ME, McCarthy JM, Chen CA, Edmond JC, Shah VS, Bosch DGM, Berry GT, Williams L, Madan-Khetarpal S, Niyazov D, Shaw-Smith C, Kovar EM, Lupo PJ, Schaaf CP. Am J Med Genet A. 2020 Apr 10. doi: 10.1002/ajmg.a.61580. PMID: 32275123.

Severity-adjusted evaluation of newborn screening on the metabolic disease course in individuals with cytosolic urea cycle disorders. Posset R, Kölker S, Gleich F, Okun JG, Gropman AL, Nagamani SCS, Scharre S, Probst J, Walter ME, Hoffmann GF, Garbade SF, Zielonka M; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) consortia study group. Mol Genet Metab. 2020 Dec;131(4):390-397. doi: 10.1016/j.ymgme.2020.10.013. Epub 2020 Nov 7.

ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus. Lerner S, Anderzhanova E, Verbitsky S, Eilam R, Kuperman Y, Tsoory M, Kuznetsov Y, Brandis A, Mehlman T, Mazkereth R; UCDC Neuropsychologists, McCarter R, Segal M, Nagamani SCS, Chen A, Erez A. Cell Rep. 2019 Nov 19;29(8):2144-2153.e7. doi: 10.1016/j.celrep.2019.10.043.

The researchers developed a laboratory mouse model with ASL deficiency in specific regions of the brain and showed that argininosuccinate lyase (ASL) is required for the normal function of the nucleus locus coeruleus (LC) in the brain. LC is the main source of norepinephrine in the brain (an important chemical messenger in the brain and a stress hormone). Loss of ASL in the LC results in low amounts of nitric oxide (NO) which leads to the reduced amount and activity of tyrosine hydroxylase (TH), an enzyme needed to produce dopamine and norepinephrine. The mice with ASL deficiency in LC showed decreased amounts of dopamine and norepinephrine in the brain, displayed higher blood pressure, increased motor activity, and increased sensitivity to develop seizures. Treatment of these mice with donor NO resulted in lower blood pressure and less seizure activity. Behavioral data previously collected from the Longitudinal Study of UCDs (Urea Cycle Disorders) conducted by the Urea Cycle Disorders Consortium showed 55% of participants with ASLD displayed lower attention spans during study visits, compared to 39.4% of participants with another UCD—argininosuccinate synthase deficiency (ASS1D/Citrullinemia). The results were similar for participants who did not have any documented episodes of hyperammonemia, which can affect behavior and cognition. Eighteen percent of participants with ASS1D without documented hyperammonemic events self-reported lower attention spans, compared to 54% of participants with ASLD. More research into the unique neurocognitive characteristics of ASLD will help improve treatment and management.

Early prediction of phenotypic severity in Citrullinemia Type 1. Zielonka M, Kölker S, Gleich F, Stützenberger N, Nagamani SCS, Gropman AL, Hoffmann GF, Garbade SF, Posset R; Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. Ann Clin Transl Neurol. 2019 Sep;6(9):1858-1871. doi: 10.1002/acn3.50886. Epub 2019 Aug 30.

Citrullinemia type1(ASS1D), also known as argininosuccinate synthase deficiency (ASS1D), is an inherited UCD that is detectable by newborn screening. The severity of the disease is variable, with health outcomes ranging from dangerous levels of hyperammonemic brain damage to mild, unnoticeable symptoms. Infant mortality rate for this disease has remained high over the decades despite the implementation of early treatment interventions. In this study, researchers evaluated a new test that could possibly predict the severity of ASS1D , based on the activity level of the enzyme argininosuccinate synthetase 1 (ASS1), which has been shown in previous studies to predict the severity of other inborn errors of metabolism. Participant data was collected from the Longitudinal Study of UCD conducted by the Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD). The researchers used a newly established assay to measure enzymatic activity of ASS1. The results showed that participants with ASS1D with ASS1 activity at 8.1% or lower experienced more frequent and severe hyperammonemic events and poorer cognitive function than participants with ASS1 activity above 8.1%. Additionally, participants with 26.6% or lower ASS1 activity had participated in special education programs, and those with 19.3% or lower ASS1 activity suffered more often from movement disorders. Participants with 4.8% or lower ASS1 activity were more likely to undergo liver transplantation. These results suggest that this enzymatic activity method could be useful in the clinical outcome prediction.

Hepatic arginase deficiency fosters dysmyelination during postnatal CNS development. Liu XB, Haney JR, Cantero G, Lambert JR, Otero-Garcia M, Truong B, Gropman A, Cobos I, Cederbaum SD, Lipshutz GS. JCI Insight. 2019 Sep 5;4(17):e130260. doi: 10.1172/jci.insight.130260.

Arginase deficiency is classified as a urea cycle disorder (UCD), as arginase is necessary in the breakdown of ammonia in the body. However, unlike other urea cycle disorders, hyperammonemia is uncommon with arginase deficiency. Complications that arise in this disorder such as paralysis, muscle stiffening, involuntary muscle contractions and overactive reflexes are also associated with cerebral palsy. Additionally, complications in arginase deficiency often occur later compared to other UCDs. In this study, researchers found that mice with arginase deficiency had abnormal myelin pattern in the brain and the spinal cord. Treatment of these arginase deficiency mice with arginase 1 gene therapy rescued these abnormal myelin patterns. Due to its unique characteristics among urea cycle disorders, the researchers suggest arginase deficiency be categorized as a leukodystrophy, a group of rare metabolic genetic disorders that affect the brain and spinal cord. This study did not label the cause of muscle and nerve failure within the disorder, yet supports the importance of ongoing neonatal screening, early intervention to normalize arginase production in the body. They also suggest that early postnatal liver-based gene therapy may be of use in preventing neurological abnormalities.

Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders. Posset R, Gropman AL, Nagamani SCS, Burrage LC, Bedoyan JK, Wong D, Berry GT, Baumgartner MR, Yudkoff M, Zielonka M, Hoffmann GF, Burgard P, Schulze A, McCandless SE, Garcia-Cazorla A, Seminara J, Garbade SF, Kölker S; Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group. Ann Neurol. 2019 Jul;86(1):116-128. doi: 10.1002/ana.25492. Epub 2019 May 13.

As intellectual and developmental disabilities are common in individuals diagnosed with urea cycle disorders (UCD), the purpose of this study was to evaluate the impact of diagnostic and treatment methods on cognitive outcomes such as thinking, reasoning, remembering, imagining, and learning. Results from neurocognitive testing of 503 individuals with UCD enrolled in the Longitudinal Study of UCD conducted by the UCD Consortium (UCDC) and the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD) from 2006 to 2016 were studied. IQ scores less than 70, indicating intellectual disability, were associated with UCD type and early disease onset. The height of initial peak plasma ammonium level was associated with poorer neurocognitive outcomes in proximal UCDs (CPS1, OTCD). Individuals with citrullinemia (argininosuccinate synthetase deficiency, ASS1D) and argininosuccinate lyase deficiency (ASLD) who were identified by newborn screening but did not have symptoms at diagnosis had better outcomes than those diagnosed after having symptoms. Additionally, early liver transplantation appeared to be beneficial.

Impairment of cognitive function in ornithine transcarbamylase deficiency is global rather than domain-specific and is associated with disease onset, sex, maximum ammonium, and number of hyperammonemic events. Buerger C, Garbade SF, Dietrich Alber F, Waisbren SE, McCarter R, Kölker S, Burgard P; Urea Cycle Disorders Consortium. J Inherit Metab Dis. 2019 Mar;42(2):243-253. doi: 10.1002/jimd.12013. Epub 2019 Jan 22.

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder (UCD). OTCD presents with a wide range of symptom severity. In this study, the number of hyperammonaemic events, clinical findings, and cognitive functioning domains—intelligence (IQ), executive function, memory, visuomotor integration and visual perception—were compared across groups. The groups were separated according to disease onset type— late disease onset (clinical symptoms at more than 28 days old), early disease onset (clinical symptoms at 28 days old or less), or asymptomatic—sex, and age. Participant information collected by the Urea Cycle Disorders Consortium (UCDC) through the Longitudinal Study between 2006 and 2014 served as the data source, to include 300 OTCD participants who underwent psychological evaluations. Although mean scores of late onset and asymptomatic individuals were within 1 SD of the population norm (IQ = 85-115, which is the normal range for individuals with-out UCD, as well), asymptomatic participants attained significantly higher scores than late onset participants and males scored higher than females. Intelligence scores proved to correlate with overall cognitive functioning. The correlation between maximum ammonia concentration and intelligence correlated significantly higher in early onset than in late onset participants (i.e. higher ammonia levels correlated with lower IQ). Correlation between the number of hyperammonemic events and intelligence scores were similar for early onset and late onset individuals. The number of clinical symptoms was significantly associated with intelligence, but not with scores in other domains. Results suggest that OTCD has a global impact on cognitive functioning rather than a specific effect on distinct cognitive domains (executive function, memory, visual-motor integration, visual perception).

Long-term safety and efficacy of glycerol phenylbutyrate for the management of urea cycle disorder patients. Diaz GA, Schulze A, Longo N, Rhead W, Feigenbaum A, Wong D, Merritt JL 2nd, Berquist W, Gallagher RC, Bartholomew D, McCandless SE, Smith WE, Harding CO, Zori R, Lichter-Konecki U, Vockley J, Canavan C, Vescio T, Holt RJ, Berry SA. Mol Genet Metab. 2019 Jul 10. pii: S1096-7192(19)30323-3. PMID: 31326288. Full Text.

Neuropsychological attributes of urea cycle disorders: A systematic review of the literature. Waisbren SE, Stefanatos AK, Kok TMY, Ozturk-Hismi B. J Inherit Metab Dis. 2019 Jul 3. PMID: 31268178, Full Text.

The m.11778 A > G variant associated with the coexistence of Leber's hereditary optic neuropathy and multiple sclerosis-like illness dysregulates the metabolic interplay between mitochondrial oxidative phosphorylation and glycolysis. Uittenbogaard M, Brantner CA, Fang Z, Wong LJ, Gropman A, Chiaramello A. Mitochondrion. 2019 May;46:187-194. doi: 10.1016/j.mito.2018.06.001. Epub 2018 Jun 8.

Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders-A successful strategy for clinical research of rare diseases. Posset R, Garbade SF, Boy N, Burlina AB, Dionisi-Vici C, Dobbelaere D, Garcia-Cazorla A, de Lonlay P, Teles EL, Vara R, Mew NA, Batshaw ML, Baumgartner MR, McCandless SE, Seminara J, Summar M, Hoffmann GF, Kölker S, Burgard P; Additional individual contributors of the UCDC and the E-IMD consortium. J Inherit Metab Dis. 2019 Jan;42(1):93-106. doi: 10.1002/jimd.12031.

Untargeted metabolomic profiling reveals multiple pathway perturbations and new clinical biomarkers in urea cycle disorders. Burrage LC, Thistlethwaite L, Stroup BM, Sun Q, Miller MJ, Nagamani SCS, Craigen W, Scaglia F, Sutton VR, Graham B, Kennedy AD; Members of the UCDC,, Milosavljevic A, Lee BH, Elsea SH. Genet Med. 2019 Sep;21(9):1977-1986. doi: 10.1038/s41436-019-0442-0. Epub 2019 Jan 23.

Urea cycle disorders (UCDs) are screened and diagnosed through the use of biochemical and molecular testing. If biomarkers of UCDs, such as elevated (higher) levels of ammonia and arginine, are present in a patient’s screening tests, an analysis of their genetic composition (makeup) will confirm the disorder. However, this may not be a reliable method of diagnosis in all cases, as ornithine transcarbamylase deficiency (OTCD) can be difficult to identify due to the nature of the disorder. Untargeted metabolomic profiling has become an important tool in diagnosis and management of UCDs because it is able to detect biomarkers of UCDs that might not be captured by the traditional methods of diagnosis. In this study, samples from 48 subjects that were collected during routine clinical visits and samples from the Urea Cycle Disorders Consortium (UCDC) Longitudinal Study were analyzed with metabolomic profiling. Results from the analyses found known biomarkers of UCDs.

"Cerebral palsy" in a patient with arginase deficiency. Jichlinski A, Clarke L, Whitehead MT, Gropman A. Semin Pediatr Neurol. 2018;26:110-114. Full Text.

A randomized trial to study the comparative efficacy of phenylbutyrate and benzoate on nitrogen excretion and ureagenesis in healthy volunteers. Nagamani SCS, Agarwal U, Tam A, Azamian M, McMeans A, Didelija IC, Mohammad MA, Marini JC. Genet Med. 2018 Jul;20(7):708-716. doi: 10.1038/gim.2017.167. Epub 2017 Oct 12.

Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension. Kho J, Tian X, Wong WT, Bertin T, Jiang MM, Chen S, Jin Z, Shchelochkov OA, Burrage LC, Reddy AK, Jiang H, Abo-Zahrah R, Ma S, Zhang P, Bissig KD, Kim JJ, Devaraj S, Rodney GG, Erez A, Bryan NS, Nagamani SCS, Lee BH. Am J Hum Genet. 2018 Aug 2;103(2):276-287. doi: 10.1016/j.ajhg.2018.07.008.

Key Point: A chemical deficiency associated with ASLD often leads to high blood pressure. Nitric oxide supplementation is currently being investigated in clinical trials as a treatment option for individuals with ASLD. In this study, the investigators used mice with argininosuccinate lyase deficiency (ASLD) and cells from patients with ASLD to study the mechanisms involved in causing high blood pressure in this disorder, which is the second most common UCD (Figure 4). The investigators show that loss of the urea cycle enzyme ASL in the lining cells of the blood vessels leads to reduction of a chemical called nitric oxide (NO) and an increase in oxidative stress that lead to vascular dysfunction. Using data from a human trial that was funded by the Urea Cycle Disorders Consortium (UCDC), they also show that the blood pressure in individuals with ASLD can be elevated. The results of this study can have potential treatment implications. Currently, nitric oxide supplementation is being investigated in clinical trials as a treatment option for individuals with ASLD.

Biochemical markers and neuropsychological functioning in distal urea cycle disorders. Waisbren SE, Cuthbertson D, Burgard P, Holbert A, McCarter R, Cederbaum S; Members of the Urea Cycle Disorders Consortium. J Inherit Metab Dis. 2018 Jul;41(4):657-667. doi: 10.1007/s10545-017-0132-5. Epub 2018 Feb 8.

The urea cycle breaks down ammonia into urea, which is then excreted (released) through urine; urea cycle disorders (UCDs) occur when a step in the urea cycle process is disrupted. Ammonia accumulation is shared amongst the different UCD types, but each individual UCD can have distinctive (unique) effects on the body. This report examines links between biochemical markers (ammonia, glutamine, arginine, citrulline) and neuropsychological test results in three UCD subtypes - argininosuccinic acid synthetase deficiency (ASD or citrullinemia type I), argininosuccinic acid lyase deficiency (ASA or ALD), and arginase deficiency (ARGD). Using data previously collected by the Urea Cycle Disorders Consortium’s Longitudinal Study, the investigators evaluated the neuropsychological tests and lab results of 145 participants (Figure 2). The neurological tests measured for intelligence (IQ), verbal and visual abilities, motor function and memory. As a result, the mean full scale IQ was below the population mean of 100 ± 15 for all groups: (ASD = 79 ± 24; ASA = 71 ± 21; ARGD = 65 ± 19), and the greatest deficits were noted in visual performance and motor skills for all groups. The biomarkers that most reliably indicated poor overall neuropsychological performance were ammonia and citrulline for ASD participants; ammonia, glutamine, and citrulline for ASA participants; and arginine, ammonia and citrulline for ARGD participants. Recognizing biomarker profiles is useful in deter-mining the most appropriate treatments.

Conducting an investigator-initiated randomized double-blinded intervention trial in acute decompensation of inborn errors of metabolism: Lessons from the N-Carbamylglutamate Consortium. Ah Mew N, Cnaan A, McCarter R, Choi H, Glass P, Rice K, Scavo L, Gillespie CW, Diaz GA, Berry GT, Wong D, Konczal L, McCandless SE, Coughlin CR, II, Weisfeld-Adams JD, Ficicioglu C, Yudkoff M, Enns GM, Lichter-Konecki U, Gallagher R, Tuchman M. Ah Mew N, Cnaan A, McCarter R, Choi H, Glass P, Rice K, Scavo L, Gillespie CW, Diaz GA, Berry GT, Wong D, Konczal L, McCandless SE., Coughlin CR, II, Weisfeld-Adams JD, Ficicioglu C, Yudkoff M, Enns GM, Lichter-Konecki U, Gallagher R, Tuchman M. Conducting an investigator-initiated randomized double-blinded intervention trial in acute decompensation of inborn errors of metabolism: Lessons from the N-Carbamylglutamate Consortium. Translational Science of Rare Diseases. 2018; 3: 157–170.

Inborn errors of metabolism (IEMs), such as urea cycle disorders (UCDs), fall within the category of ultra-rare disorders in which 1 in 50,000 people have the disorder, many of whom die during childhood. This publication focuses on the challenges the N-carbamylglutamate Consortium (NCGC) faced while conducting two trials for N-carbamylglutamate (NCG), an approved treatment for N-acetylglutamate synthetase (NAGS) deficiency, one of the UCD subtypes that causes hyperammonemia. Among the topics discussed is the difficulty of recruiting and retaining eligible participants; enrollment numbers are largely affected by the small participant selection pools characteristic of rare diseases and missed opportunities to refer patients to open studies during routine clinical visits. It is preferable to enroll participants during non-crisis situations in order to avoid an exaggeration of the expected number of hyperammonemia events that could occur during a study. Partnerships with patient advocacy groups such as the National Urea Cycle Disorders Foundation (NUCDF) are crucial for rare disease studies as they pro-vide opportunities for researchers to educate and reach out to potential participants and their families and caregivers. Introspective publications such as this are valuable in the evaluation and improvement of study methods.

Epigenetic modifiers promote mitochondrial biogenesis and oxidative metabolism leading to enhanced differentiation of neuroprogenitor cells. Uittenbogaard M, Brantner CA, Chiaramello A. Cell Death Dis. 2018 Mar 2;9(3):360. doi: 10.1038/s41419-018-0396-1.

Human heterologous liver cells transiently improve hyperammonemia and ureagenesis in individuals with severe urea cycle disorders. Meyburg J, Opladen T, Spiekerkötter U, Schlune A, Schenk JP, Schmidt J, Weitz J, Okun J, Bürger F, Omran TB, Abdoh G, Al Rifai H, Monavari A, Konstantopoulou V, Kölker S, Yudkoff M, Hoffmann GF. J Inherit Metab Dis. 2018;41:81-90. PMID: 29027067.

Newborn screening for proximal urea cycle disorders: Current evidence supporting recommendations for newborn screening. Merritt JL 2nd, Brody LL, Pino G, Rinaldo P. Mol Genet Metab. 2018 Jun;124(2):109-113. doi: 10.1016/j.ymgme.2018.04.006. Epub 2018 Apr 20. PubMed PMID: 29703588.

Novel insights into the functional metabolic impact of an apparent de novo m.8993T>G variant in the MT-ATP6 gene associated with maternally inherited form of Leigh Syndrome. Uittenbogaard M, Brantner CA, Fang Z, Wong LC, Gropman A, Chiaramello A. Mol Genet Metab. 2018 May;124(1):71-81. doi: 10.1016/j.ymgme.2018.03.011. Epub 2018 Mar 27.

Novel metabolic signatures of compound heterozygous Szt2 variants in a case of early-onset of epileptic encephalopathy. Uittenbogaard M, Gropman A, Brantner CA, Chiaramello A. Clin Case Rep. 2018 Oct 25;6(12):2376-2384. doi: 10.1002/ccr3.1868. eCollection 2018 Dec.

The utility of EEG monitoring in neonates with hyperammonemia due to inborn errors of metabolism. Wiwattanadittakul N, Prust M, Gaillard WD, Massaro A, Vezina G, Tsuchida TN, Gropman AL. Mol Genet Metab. 2018 Nov;125(3):235-240. doi: 10.1016/j.ymgme.2018.08.011. Epub 2018 Aug 24.

Continuous video electroencephalogram (cvEEG) is the long-term video monitoring of electrical activity in the brain. The typical length of an electroencephalogram (EEG) test is between 30 to 60 minutes, where as a cvEEG test can last for days at a time. Most infant seizures do not have clinical symptoms and can only be detected by an EEG, making cvEEG the preferred method for monitoring seizures associated with acute brain injury; however, the benefits of using cvEEG on infants with in-born errors of metabolism have not been determined. In this study, researchers analyzed the medical records of eight infants who experienced hyperammonemia due to inborn errors of metabolism and received prolonged EEG tests at Children's National Medical Center, Washington, D.C., between January 2009 and March 2017. The results showed that seven of the infants had seizures, and six had seizures that could only be detected by EEG. Although there was evidence that elevated levels of blood ammonia and glutamine—common symptoms of urea cycle disorders—had a possible connection to seizure activity on EEG, it is important to note that some of the infants, after receiving medication that normalized their blood ammonia and glutamine levels, continued to have seizures (Figure 5). Seizures were also detected by EEG before blood ammonia levels spiked and occurred within 24 to 36 hours of clinical symptoms. These and other findings documented in the study suggest the importance of long-term cvEEG in the evaluation of inborn errors of metabolism.

Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders – a successful strategy for clinical research of rare diseases. Posset R, Garbade SF, Boy N, Burlina AB, Dionisi-Vici C, Dobbelaere D, Garcia-Cazorla A, de Lonlay P, Teles EL, Vara R, Ah Mew N, Batshaw ML, Baumgartner MR, McCandless SE, Seminara J, Summar ML, Hoffmann GF, Kölker S, Burgard P; on behalf of the UCDC and the E-IMD consortium. J Inherit Metab Dis. 2018 Jul 4. PMID: 29974348.

The Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication Type Metabolic Disorders (E-IMD) collaborated to compare the prevalence and characteristics of urea cycle disorders (UCDs) in North America and Europe. The UCDC Longitudinal Study data was used for North America. Combining registries from both consortia, researchers looked at the medical histories of over 1,000 patients with UCD for information such as UCD type, late disease onset (clinical symptoms at more than 28 days old) or early dis-ease onset (clinical symptoms at 28 days old or less), and age of diagnosis. In North America and Europe, Ornithine Transcarbamylase Deficiency (OTCD ) and late disease onset were the most common; however, the lack of early onset reports may have been caused by the voluntary nature of the registries, as the severe symptoms associated with early onset UCDs could make participation more difficult. The data also showed that the delay between age of clinical symptoms and age of diagnosis was shorter for early onset patients, which was likely due to the higher visibility of symptoms such as seizures.

Transplantation of Gene-Edited Hepatocyte-like Cells Modestly Improves Survival of Arginase-1-Deficient Mice. Sin YY, Ballantyne LL, Richmond CR, Funk CD. Mol Ther Nucleic Acids. 2018 Mar 2;10:122-130. doi: 10.1016/j.omtn.2017.11.012. Epub 2017 Dec 1.

This study, funded by a Urea Cycle Disorders Consortium (UCDC) training grant, focused on the possibility of incorporating gene editing in a preclinical animal model for treatment of urea cycle disorder (UCD), specifically arginase deficiency. Induced pluripotent stem cells (iPSCs), or cells that can become any type of cell in the body, were turned into hepatocyte-like cells (HLCs), or liver cells. The HLCs were transplanted into mice with arginase deficiency, and investigators monitored the mice for signs that the HLCs were producing arginase enzyme. The results showed 5% liver regeneration, low productions of arginase, and a maximum lifespan of 22 days compared to 14 days in arginase-deficient mice that were not trans-planted. Although the initial proof of concept study showed minimal improvements, the research suggests that there might be a place for such therapies in the future.

Urea Cycle Disorders. *Lindsay C, Burrage, Brendan Lee, and Sandesh C, S Nagamani. Rudolph Pediatrics, Chapter 141, p 23rd Edition, McGraw Hill, 2018.

Glycerol phenylbutyrate for the maintenance treatment of patients with deficiencies in enzymes of the urea cycle. Longo N , Holt RJ. Expert Opin. on Orphan Drugs, 5 (12) (2017), pp. 999-1010. Full Text.

Hyperammonemia in Neonates: Looking beyond sepsis. Schrier Vergano SA, Le Mons C. Neonatology Today 2017 Dec, Vol 13/Issue 12, pp 15-16. Online Full Text.

Incidence, disease onset and short-term outcome in urea cycle disorders -cross-border surveillance in Germany, Austria and Switzerland. Nettesheim S, Kölker S, Karall D, Häberle J, Posset R, Hoffmann GF, Heinrich B, Gleich F, Garbade SF; Arbeitsgemeinschaft für Pädiatrische Stoffwechselstörungen (APS); European registry and network for Intoxication type Metabolic Diseases (E-IMD); Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland (ESPED); Austrian Metabolic Group; Swiss Paediatric Surveillance Unit (SPSU). Orphanet J Rare Dis. 2017;12:111. PMID: 28619060, PMCID: PMC5472961.

Precision medicine in rare disease: Mechanisms of disparate effects of N-carbamyl-l-glutamate on mutant CPS1 enzymes. Shi D, Zhao G, Ah Mew N, Tuchman M. Mol Genet Metab. 2017 Mar;120(3):198–206. PMID: 28007335, PMCID: PMC5346444.

Proof-of-Concept Gene Editing for the Murine Model of Inducible Arginase-1 Deficiency. Sin YY, Price PR, Ballantyne LL, Funk CD. Sci Rep. 2017 May 31;7(1):2585. doi: 10.1038/s41598-017-02927-2.

Safety and efficacy of glycerol phenylbutyrate for management of urea cycle disorders in patients aged 2 months to 2 years. Berry SA, Longo N, Diaz GA, McCandless SE, Smith WE, Harding CO, Zori R, Ficicioglu C, Lichter-Konecki U, Robinson B, Vockley J. Mol Genet Metab. 2017;122(3):46-53. PMID: 28916119, Full Text.

Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders. Posset R, Garcia-Cazorla A, Valayannopoulos V, Teles EL, Dionisi-Vici C, Brassier A, Burlina AB, Burgard P, Cortès-Saladelafont E, Dobbelaere D, Couce ML, Sykut-Cegielska J, Häberle J, Lund AM, Chakrapani A, Schiff M, Walter JH, Zeman J, Vara R, Kölker S, additional individual contributors of the E-IMD consortium. J Inherit Metab Dis. 2016;39:661-672. PMID: 27106216.

Barriers to drug adherence in the treatment of urea cycle disorders: assessment of patient, caregiver and provider perspectives. Shchelochkov OA ,Dickinson K , Scharschmidt BF , Lee B, Marino M, Le Mons C. Mol Genet and Metab Rep., 8 (2016 Sep), pp. 43-47. PMID: 27493880,  PMCID: PMC4963256.

Behavioural and emotional problems, intellectual impairment and health-related quality of life in patients with organic acidurias and urea cycle disorders. Jamiolkowski D, Kölker S, Glahn EM, Barić I, Zeman J, Baumgartner MR, Mühlhausen C, Garcia-Cazorla A, Gleich F, Haege G, Burgard P; E-IMD consortium. J Inherit Metab Dis. 2016; 39: 231-41. PMID: 26310964.

Brain biomarkers and neuroimaging to diagnose urea cycle disorders and assess prognosis. Barkovich E, Robinson C, Gropman A. Expert Opinion on Orphan Drugs, 4:11, 1123-1132. Abstract.

Elevations of C14:1 and C14:2 Plasma Acylcarnitines in Fasted Children: A Diagnostic Dilemma. Burrage LC, Miller MJ, Wong LJ, Kennedy AD, Sutton VR, Sun Q, Elsea SH, Graham BH. J Pediatr. 2016 Feb;169:208-13.e2. doi: 10.1016/j.jpeds.2015.10.045. Epub 2015 Nov 18.

Executive functioning profiles from the BRIEF across pediatric medical disorders: Age and diagnosis factors. Krivitzky LS, Walsh KS, Fisher EL, Berl MM. Child Neuropsychol. 2016;22(7):870-88. doi: 10.1080/09297049.2015.1054272. Epub 2015 Jul 6.

Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD). Laemmle A, Gallagher RC, Keogh A, Stricker T, Gautschi M, Nuoffer JM, Baumgartner MR, Häberle J. PLoS One. 2016 Apr 12;11(4):e0153358. doi: 10.1371/journal.pone.0153358. eCollection 2016.

Glutamine and hyperammonemic crises in patients with urea cycle disorders. Lee B, Diaz GA, Rhead W, Lichter-Konecki U, Feigenbaum A, Berry SA, Le Mons C, Bartley J, Longo N, Nagamani SC, Berquist W, Gallagher RC, Harding CO, McCandless SE, Smith W, Schulze A, Marino M, Rowell R, Coakley DF, Mokhtarani M, Scharschmidt BF. Mol Genet Metab. 2016 Jan;117(1):27-32. doi: 10.1016/j.ymgme.2015.11.005. Epub 2015 Nov 11.

Growth Charts for Prader-Willi Syndrome During Growth Hormone Treatment. Butler MG, Lee J, Cox DM, Manzardo AM, Gold JA, Miller JL, Roof E, Dykens E, Kimonis V, Driscoll DJ. Clin Pediatr (Phila). 2016 Sep;55(10):957-74. doi: 10.1177/0009922815617973. Epub 2016 Feb 3.

Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium. Waisbren SE, Gropman AL; Members of the Urea Cycle Disorders Consortium (UCDC), Batshaw ML. J Inherit Metab Dis. 2016 Jul;39(4):573-84. doi: 10.1007/s10545-016-9942-0. Epub 2016 May 23.

In vivo monitoring of urea cycle activity with (13)C-acetate as a tracer of ureagenesis. Opladen T, Lindner M, Das AM, Marquardt T, Khan A, Emre SH, Burton BK, Barshop BA, Böhm T, Meyburg J, Zangerl K, Mayorandan S, Burgard P, Dürr UH, Rosenkranz B, Rennecke J, Derbinski J, Yudkoff M, Hoffmann GF. Mol Genet Metab. 2016 Jan;117(1):19-26. doi: 10.1016/j.ymgme.2015.11.007. Epub 2015 Nov 14.

Neurocognitive clinical outcome assessments for inborn errors of metabolism and other rare conditions. Shapiro E, Bernstein J, Adams HR, Barbier AJ, Buracchio T, Como P, Delaney KA, Eichler F, Goldsmith JC, Hogan M, Kovacs S, Mink JW, Odenkirchen J, Parisi MA, Skrinar A, Waisbren SE, Mulberg AE. Mol Genet Metab. 2016 Jun;118(2):65-9. doi: 10.1016/j.ymgme.2016.04.006. Epub 2016 Apr 14.

Nineteen-year follow-up of a patient with severe glutathione synthetase deficiency. Atwal PS, Medina CR, Burrage LC, Sutton VR. J Hum Genet. 2016 Jul;61(7):669-72. doi: 10.1038/jhg.2016.20. Epub 2016 Mar 17.

The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Merkel PA, Manion M, Gopal-Srivastava R, Groft S, Jinnah HA, Robertson D, Krischer JP; Rare Diseases Clinical Research Network. Orphanet J Rare Dis. 2016 May 18;11(1):66. doi: 10.1186/s13023-016-0445-8.

Arginase-1 deficiency. *Sin YY, Baron G, Schulze A, Funk CD. J Mol Med (Berl). 2015 Dec;93(12):1287-96. PMID: 26467175.

Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3. Chong JX, Burrage LC, Beck AE, Marvin CT, McMillin MJ, Shively KM, Harrell TM, Buckingham KJ, Bacino CA, Jain M, Alanay Y, Berry SA, Carey JC, Gibbs RA, Lee BH, Krakow D, Shendure J, Nickerson DA; University of Washington Center for Mendelian Genomics, Bamshad MJ. Am J Hum Genet. 2015 May 7;96(5):841-9. doi: 10.1016/j.ajhg.2015.04.004.

Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder. Lee B, Diaz GA, Rhead W, Lichter-Konecki U, Feigenbaum A, Berry SA, Le Mons C, Bartley JA, Longo N, Nagamani SC, Berquist W, Gallagher R, Bartholomew D, Harding CO, Korson MS, McCandless SE, Smith W, Cederbaum S, Wong D, Merritt JL 2nd, Schulze A, Vockley J, Kronn D, Zori R, Summar M, Milikien DA, Marino M, Coakley DF, Mokhtarani M; UCD Consortium, Scharschmidt BF. Genet Med. 2015 Jul;17(7):561-8. doi: 10.1038/gim.2014.148. Epub 2014 Dec 11.

Catel-Manzke Syndrome: Further Delineation of the Phenotype Associated with Pathogenic Variants in TGDS. Pferdehirt R, Jain M, Blazo MA, Lee B, Burrage LC. Mol Genet Metab Rep. 2015 Sep 1;4:89-91. doi: 10.1016/j.ymgmr.2015.08.003.

De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome. Burrage LC, Charng WL, Eldomery MK, Willer JR, Davis EE, Lugtenberg D, Zhu W, Leduc MS, Akdemir ZC, Azamian M, Zapata G, Hernandez PP, Schoots J, de Munnik SA, Roepman R, Pearring JN, Jhangiani S, Katsanis N, Vissers LE, Brunner HG, Beaudet AL, Rosenfeld JA, Muzny DM, Gibbs RA, Eng CM, Xia F, Lalani SR, Lupski JR, Bongers EM, Yang Y. Am J Hum Genet. 2015 Dec 3;97(6):904-13. doi: 10.1016/j.ajhg.2015.11.006.

From Genome to Structure and Back Again: A Family Portrait of the Transcarbamylases. Shi D, Allewell NM, Tuchman M. Int J Mol Sci. 2015 Aug 12;16(8):18836-64. doi: 10.3390/ijms160818836.

Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. Caldovic L, Abdikarim I, Narain S, Tuchman M, Morizono H. J Genet Genomics. 2015 May 20;42(5):181-94. doi: 10.1016/j.jgg.2015.04.003. Epub 2015 May 19.

Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency. Burrage LC, Sun Q, Elsea SH, Jiang MM, Nagamani SC, Frankel AE, Stone E, Alters SE, Johnson DE, Rowlinson SW, Georgiou G; Members of Urea Cycle Disorders Consortium, Lee BH. Hum Mol Genet. 2015 Nov 15;24(22):6417-27. doi: 10.1093/hmg/ddv352. Epub 2015 Sep 10.

Impact of age at onset and newborn screening on outcome in organic acidurias. Heringer J, Valayannopoulos V, Lund AM, Wijburg FA, Freisinger P, Barić I, Baumgartner MR, Burgard P, Burlina AB, Chapman KA, I Saladelafont EC, Karall D, Mühlhausen C, Riches V, Schiff M, Sykut-Cegielska J, Walter JH, Zeman J, Chabrol B, Kölker S, additional individual contributors of the E-IMD consortium. J Inherit Metab Dis. 2015 Dec 21. PMID: 26689403, Full Text (with PubMed access).

Inherited Metabolic Disorders: Aspects of Chronic Nutrition Management. Boyer SW, Barclay LJ, Burrage LC. Nutr Clin Pract. 2015 Aug;30(4):502-10. doi: 10.1177/0884533615586201. Epub 2015 Jun 16.

Networking across borders for individuals with organic acidurias and urea cycle disorders: The E-IMD Consortium. Kolker S, Dobbelaere D, Haberle J, Burgard P, Gleich F, Summar ML, Hannigan S, Parker S, Chakrapani A, Baumgartner MR, and on behalf of the E-IMD Consortium. JIMD Reports. 2015;22:29-38. PMID: 25701269, PMCID: PMC4486274.

Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Miller MJ, Burrage LC, Gibson JB, Strenk ME, Lose EJ, Bick DP, Elsea SH, Sutton VR, Sun Q, Graham BH, Craigen WJ, Zhang VW, Wong LJ. Mol Genet Metab. 2015 Nov;116(3):139-45. doi: 10.1016/j.ymgme.2015.08.011. Epub 2015 Sep 2.

Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency. Pacheco-Colón I, Washington SD, Sprouse C, Helman G, Gropman AL, VanMeter JW. PLoS One. 2015 Jun 11;10(6):e0129595. doi: 10.1371/journal.pone.0129595. eCollection 2015.

Role of brain imaging for demonstrating ammonia-induced changes. Pacheco-Colón Ileana, Fricke Stanley and Gropman Andrea. In Current Approach to Hyperammonemia. Johannes Häberle (ed). eBook, Future Medicine. 2014.

Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials. Nagamani SC, Diaz GA, Rhead W, Berry SA, Le Mons C, Lichter-Konecki U, Bartley J, Feigenbaum A, Schulze A, Longo N, Berquist W, Gallagher R, Bartholomew D, Harding CO, Korson MS, McCandless SE, Smith W, Vockley J, Kronn D, Zori R, Cederbaum S, Merritt JL 2nd, Wong D, Coakley DF, Scharschmidt BF, Dickinson K, Marino M, Lee BH, Mokhtarani M. Mol Genet Metab. 2015 Sep-Oct;116(1-2):29-34. doi: 10.1016/j.ymgme.2015.08.002. Epub 2015 Aug 5.

Strategies to rescue the consequences of inducible arginase-1 deficiency in mice. *Ballantyne LL, Sin YY, St Amand T, Si J, Goossens S, Haenebalcke L, Haigh JJ, Kyriakopoulou L, Schulze A, Funk CD. PLoS One. 2015 May 4;10(5):e0125967. PMID: 25938595, PMCID: PMC4418594.

Structures of the N-acetyltransferase domain of Xylella fastidiosa N-acetyl-L-glutamate synthase/kinase with and without a His tag bound to N-acetyl-L-glutamate. Zhao G, Jin Z, Allewell NM, Tuchman M, Shi D. Acta Crystallogr F Struct Biol Commun. 2015 Jan 1;71(Pt 1):86-95. doi: 10.1107/S2053230X14026788. Epub 2015 Jan 1.

The N-Acetylglutamate Synthase Family: Structures, Function and Mechanisms. Shi D, Allewell NM, Tuchman M. Int J Mol Sci. 2015 Jun 9;16(6):13004-22. doi: 10.3390/ijms160613004.

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. Kolker S, Garcia-Cazorla A, Valayannopoulos V, Lund AM, Burlina AB, Sykut-Cegielska J, Wijburg FA, Teles EL, Zeman J, Dionisi-Vici C, Barić I, Karall D, Augoustides-Savvopoulou P, Aksglaede L, Arnoux JB, Avram P, Baumgartner MR, Blasco-Alonso J, Chabrol B, Chakrapani A, Chapman K, I Saladelafont EC, Couce ML, de Meirleir L, Dobbelaere D, Dvorakova V, Furlan F, Gleich F, Gradowska W, Grünewald S, Jalan A, Häberle J, Haege G, Lachmann R, Laemmle A, Langereis E, de Lonlay P, Martinelli D, Matsumoto S, Mühlhausen C, de Baulny HO, Ortez C, Peña-Quintana L, Ramadža DP, Rodrigues E, Scholl-Bürgi S, Sokal E, Staufner C, Summar ML, Thompson N, Vara R, Pinera IV, Walter JH, Williams M, Burgard P. J Inherit Metab Dis. 2015 Nov;38(6):1041-1057. PMID: 25875215, Full Text  (with PubMed access).

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype. Kolker S, Valayannopoulos V, Burlina AB, Sykut-Cegielska, Wijburg FA, Teles EL, Zeman J, Dionisi-Vici C, Barić I, Karall D, Arnoux JB, Avram P, Baumgartner MR, Blasco-Alonso J, Boy SP, Rasmussen MB, Burgard P, Chabrol B, Chakrapani A, Chapman K, Cortès I Saladelafont E, Couce ML, de Meirleir L, Dobbelaere D, Furlan F, Gleich F, González MJ, Gradowska W, Grünewald S, Honzik T, Hörster F, Ioannou H, Jalan A, Häberle J, Haege G, Langereis E, de Lonlay P, Martinelli D, Matsumoto S, Mühlhausen C, Murphy E, de Baulny HO, Ortez C, Pedrón CC, Pintos-Morell G, Pena-Quintana L, Ramadža DP, Rodrigues E, Scholl-Bürgi S, Sokal E, Summar ML, Thompson N, Vara R, Pinera IV, Walter JH, Williams M, Lund AM, Garcia-Cazorla A. J Inherit Metab Dis. 2015 Nov;38(6):1059-1074. PMID: 25875216, Full Text (with PubMed access).

A longitudinal study of urea cycle disorders. Batshaw ML, Tuchman M, Summar M, Seminara J; Members of the Urea Cycle Disorders Consortium. Mol Genet Metab. 2014 Sep-Oct;113(1-2):127-30. doi: 10.1016/j.ymgme.2014.08.001. Epub 2014 Aug 10.

Advances in urea cycle neuroimaging: Proceedings from the 4th International Symposium on urea cycle disorders, Barcelona, Spain, September 2013. Pacheco-Colón I, Fricke S, VanMeter J, Gropman AL. Mol Genet Metab. 2014 Sep-Oct;113(1-2):118-26. doi: 10.1016/j.ymgme.2014.05.005. Epub 2014 May 20.

Augmenting ureagenesis in patients with partial carbamyl phosphate synthetase 1 deficiency with N-carbamyl-L-glutamate. Ah Mew N, McCarter R, Daikhin Y, Lichter-Konecki U, Nissim I, Yudkoff M, Tuchman M. J Pediatr. 2014 Aug;165(2):401-403.e3. doi: 10.1016/j.jpeds.2014.04.012. Epub 2014 May 29.

Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Burrage LC, Nagamani SC, Campeau PM, Lee BH. Hum Mol Genet. 2014 Sep 15;23(R1):R1-8. doi: 10.1093/hmg/ddu123. Epub 2014 Mar 20.

Expression pattern and biochemical properties of zebrafish N-acetylglutamate synthase. Caldovic L, Haskins N, Mumo A, Majumdar H, Pinter M, Tuchman M, Krufka A. PLoS One. 2014 Jan 22;9(1):e85597. doi: 10.1371/journal.pone.0085597. eCollection 2014.

Genomics in newborn screening. Landau YE, Lichter-Konecki U, Levy HL. J Pediatr. 2014 Jan;164(1):14-9. doi: 10.1016/j.jpeds.2013.07.028. Epub 2013 Aug 27.

Glycerol phenylbutyrate treatment in children with urea cycle disorders: pooled analysis of short and long-term ammonia control and outcomes. Berry SA, Lichter-Konecki U, Diaz GA, McCandless SE, Rhead W, Smith W, Lemons C, Nagamani SC, Coakley DF, Mokhtarani M, Scharschmidt BF, Lee B. Mol Genet Metab. 2014 May;112(1):17-24. doi: 10.1016/j.ymgme.2014.02.007. Epub 2014 Feb 21.

Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency. Sprouse C, King J, Helman G, Pacheco-Colón I, Shattuck K, Breeden A, Seltzer R, VanMeter JW, Gropman AL. Mol Genet Metab. 2014 Sep-Oct;113(1-2):136-41. doi: 10.1016/j.ymgme.2014.05.007. Epub 2014 May 20.

Research into rare diseases of childhood. Batshaw ML, Groft SC, Krischer JP. JAMA. 2014 May 7;311(17):1729-30. doi: 10.1001/jama.2013.285873.

Significant hepatic involvement in patients with ornithine transcarbamylase deficiency. Gallagher RC, Lam C, Wong D, Cederbaum S, Sokol RJ. J Pediatr. 2014 Apr;164(4):720-725.e6. doi: 10.1016/j.jpeds.2013.12.024. Epub 2014 Jan 30.

Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders. Burrage LC, Jain M, Gandolfo L, Lee BH; Members of the Urea Cycle Disorders Consortium, Nagamani SC. Mol Genet Metab. 2014 Sep-Oct;113(1-2):131-5. doi: 10.1016/j.ymgme.2014.06.005. Epub 2014 Jul 3.

Stable isotopes in the diagnosis and treatment of inherited hyperammonemia. Mew NA, Yudkoff M, Tuchman M. J Pediatr Biochem. 2014 Jan 1;4(1):57-63. doi: 10.3233/JPB-140106.

The urea cycle disorders. Helman G, Pacheco-Colón I, Gropman AL. Semin Neurol. 2014 Jul;34(3):341-9. doi: 10.1055/s-0034-1386771. Epub 2014 Sep 5.

A decisional space for fMRI pattern separation using the principal component analysis--a comparative study of language networks in pediatric epilepsy. You X, Adjouadi M, Wang J, Guillen MR, Bernal B, Sullivan J, Donner E, Bjornson B, Berl M, Gaillard WD. Hum Brain Mapp. 2013 Sep;34(9):2330-42. doi: 10.1002/hbm.22069. Epub 2012 Mar 28.

A dynamical approach toward understanding mechanisms of team science: change, kinship, tension, and heritage in a transdisciplinary team. Lotrecchiano, GR. Clin Transl Sci. 2013 Aug;6(4): 267–278. PMID: 23919361, PMCID: PMC5350836.

Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: an fMRI study. Gropman AL, Shattuck K, Prust MJ, Seltzer RR, Breeden AL, Hailu A, Rigas A, Hussain R, VanMeter J. Hum Brain Mapp. 2013 Apr;34(4):753-61. doi: 10.1002/hbm.21470. Epub 2011 Nov 23.

Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, Longo N, Berquist W, Berry SA, Gallagher R, Lichter-Konecki U, Bartholomew D, Harding CO, Cederbaum S, McCandless SE, Smith W, Vockley G, Bart SA, Korson MS, Kronn D, Zori R, Merritt JL 2nd, C S Nagamani S, Mauney J, Lemons C, Dickinson K, Moors TL, Coakley DF, Scharschmidt BF, Lee B. Hepatology. 2013 Jun;57(6):2171-9. doi: 10.1002/hep.26058. Epub 2013 Jan 3.

Ammonia control in children ages 2 months through 5 years with urea cycle disorders: comparison of sodium phenylbutyrate and glycerol phenylbutyrate. Smith W, Diaz GA, Lichter-Konecki U, Berry SA, Harding CO, McCandless SE, LeMons C, Mauney J, Dickinson K, Coakley DF, Moors T, Mokhtarani M, Scharschmidt BF, Lee B. J Pediatr. 2013 Jun;162(6):1228-34, 1234.e1. doi: 10.1016/j.jpeds.2012.11.084. Epub 2013 Jan 13.

Clinical outcomes of neonatal onset proximal versus distal urea cycle disorders do not differ. Ah Mew N, Krivitzky L, McCarter R, Batshaw M, Tuchman M; Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. J Pediatr. 2013 Feb;162(2):324-9.e1. doi: 10.1016/j.jpeds.2012.06.065. Epub 2012 Aug 15.

Crystal structure of the N-acetyltransferase domain of human N-acetyl-L-glutamate synthase in complex with N-acetyl-L-glutamate provides insights into its catalytic and regulatory mechanisms. Zhao G, Jin Z, Allewell NM, Tuchman M, Shi D. PLoS One. 2013 Jul 24;8(7):e70369. doi: 10.1371/journal.pone.0070369. Print 2013.

Development of an animal model of nephrocalcinosis via selective dietary sodium and chloride depletion. Tuchman S, Asico LD, Escano C, Bobb DA, Ray PE. Pediatr Res. 2013 Feb;73(2):194-200. doi: 10.1038/pr.2012.172. Epub 2012 Nov 22.

Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio. Mokhtarani M, Diaz GA, Rhead W, Berry SA, Lichter-Konecki U, Feigenbaum A, Schulze A, Longo N, Bartley J, Berquist W, Gallagher R, Smith W, McCandless SE, Harding C, Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS Jr, Dickinson K, Moors T, Norris C, Coakley D, Milikien DA, Nagamani SC, Lemons C, Lee B, Scharschmidt BF. Mol Genet Metab. 2013 Dec;110(4):446-53. doi: 10.1016/j.ymgme.2013.09.017. Epub 2013 Oct 8.

Feasibility of adjunct therapeutic hypothermia treatment for hyperammonemia and encephalopathy due to urea cycle disorders and organic acidemias. Lichter-Konecki U, Nadkarni V, Moudgil A, Cook N, Poeschl J, Meyer MT, Dimmock D, Baumgart S. Mol Genet Metab. 2013 Aug;109(4):354-9. doi: 10.1016/j.ymgme.2013.05.014. Epub 2013 May 29.

Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism. *Sin YY, Ballantyne LL, Mukherjee K, St Amand T, Kyriakopoulou L, Schulze A, Funk CD. PLoS One. 2013;8(11):e80001. PMID: 24224027, PMCID: PMC3817112.

Infectious precipitants of acute hyperammonemia are associated with indicators of increased morbidity in patients with urea cycle disorders. McGuire PJ, Lee HS; members of the Urea Cycle Disorders Consoritum, Summar ML. J Pediatr. 2013 Dec;163(6):1705-1710.e1. doi: 10.1016/j.jpeds.2013.08.029. Epub 2013 Sep 29.

Magnetic resonance imaging findings and neurodevelopmental outcomes in neonates with urea-cycle defects. Gunz AC, Choong K, Potter M, Miller E. Int Med Case Rep J., 6 (2013 08/19), pp. 41-48. PMID: 23983495, PMCID: PMC3751504.

Ornithine Transcarbamylase Deficiency. Lichter-Konecki U, Caldovic L, Morizono H, Simpson K. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013. 2013 Aug 29. PMID: 24006547, Full Text.

Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Ferriero R, Manco G, Lamantea E, Nusco E, Ferrante MI, Sordino P, Stacpoole PW, Lee B, Zeviani M, Brunetti-Pierri N. Sci Transl Med. 2013 Mar 6;5(175):175ra31. doi: 10.1126/scitranslmed.3004986.

Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders. Monteleone JP, Mokhtarani M, Diaz GA, Rhead W, Lichter-Konecki U, Berry SA, Lemons C, Dickinson K, Coakley D, Lee B, Scharschmidt BF. J Clin Pharmacol. 2013 Jul;53(7):699-710. doi: 10.1002/jcph.92. Epub 2013 Jun 15.

Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. Cartagena A, Prasad AN, Rupar CA, Strong M, Tuchman M, Ah Mew N, Prasad C. Can J Neurol Sci. 2013 Jan;40(1):3-9. doi: 10.1017/s0317167100012877.

Structure of N-acetyl-L-glutamate synthase/kinase from Maricaulis maris with the allosteric inhibitor L-arginine bound. Zhao G, Haskins N, Jin Z, M Allewell N, Tuchman M, Shi D. Biochem Biophys Res Commun. 2013 Aug 9;437(4):585-90. doi: 10.1016/j.bbrc.2013.07.003. Epub 2013 Jul 10.

Structure of the complex of Neisseria gonorrhoeae N-acetyl-L-glutamate synthase with a bound bisubstrate analog. Zhao G, Allewell NM, Tuchman M, Shi D. Biochem Biophys Res Commun. 2013 Jan 25;430(4):1253-8. doi: 10.1016/j.bbrc.2012.12.064. Epub 2012 Dec 20.

The incidence of urea cycle disorders. Summar ML, Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, Kirmse B; European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD) Electronic address: http://wwwe-imdorg/en/indexphtml; Members of the Urea Cycle Disorders Consortium (UCDC) Electronic address: http://rarediseasesnetworkepiusfedu/ucdc/. Mol Genet Metab. 2013 Sep-Oct;110(1-2):179-80. doi: 10.1016/j.ymgme.2013.07.008. Epub 2013 Jul 18.

Urea cycle defects and hyperammonemia: effects on functional imaging. Gropman AL, Prust M, Breeden A, Fricke S, VanMeter J. Metab Brain Dis. 2013 Jun;28(2):269-75. doi: 10.1007/s11011-012-9348-0. Epub 2012 Nov 13.

Vector sequences are not detected in tumor tissue from research subjects with ornithine transcarbamylase deficiency who previously received adenovirus gene transfer. Zhong L, Li S, Li M, Xie J, Zhang Y, Lee B, Batshaw ML, Wilson JM, Gao G. Hum Gene Ther. 2013 Sep;24(9):814-9. doi: 10.1089/hum.2013.118.

A randomized controlled trial to evaluate the effects of high-dose versus low-dose of arginine therapy on hepatic function tests in argininosuccinic aciduria. Nagamani SC, Shchelochkov OA, Mullins MA, Carter S, Lanpher BC, Sun Q, Kleppe S, Erez A, O'Brian Smith E, Marini JC; Members of the Urea Cycle Disorders Consortium, Lee B. Mol Genet Metab. 2012 Nov;107(3):315-21. doi: 10.1016/j.ymgme.2012.09.016. Epub 2012 Sep 17.

Argininosuccinate lyase deficiency. Nagamani SC, Erez A, Lee B. Genet Med. 2012 May;14(5):501-7. doi: 10.1038/gim.2011.1. Epub 2012 Jan 5.

Conserved steroid hormone homology converges on nuclear factor κB to modulate inflammation in asthma. Payne AS, Freishtat RJ. J Investig Med. 2012 Jan;60(1):13-7. doi: 10.2310/JIM.0b013e31823d7989.

Hepatocellular carcinoma in a research subject with ornithine transcarbamylase deficiency. Wilson JM, Shchelochkov OA, Gallagher RC, Batshaw ML. Mol Genet Metab. 2012 Feb;105(2):263-5. doi: 10.1016/j.ymgme.2011.10.016. Epub 2011 Nov 7.

Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Nagamani SC, Campeau PM, Shchelochkov OA, Premkumar MH, Guse K, Brunetti-Pierri N, Chen Y, Sun Q, Tang Y, Palmer D, Reddy AK, Li L, Slesnick TC, Feig DI, Caudle S, Harrison D, Salviati L, Marini JC, Bryan NS, Erez A, Lee B. Am J Hum Genet. 2012 May 4;90(5):836-46. doi: 10.1016/j.ajhg.2012.03.018. Epub 2012 Apr 26.

Optimizing therapy for argininosuccinic aciduria. Nagamani SC, Lee B, Erez A. Mol Genet Metab. 2012 Sep;107(1-2):10-4. doi: 10.1016/j.ymgme.2012.07.009. Epub 2012 Jul 20.

Patterns of brain injury in inborn errors of metabolism. Gropman AL. Semin Pediatr Neurol. 2012 Dec;19(4):203-10. doi: 10.1016/j.spen.2012.09.007.

Peptide tyrosine tyrosine levels are increased in patients with urea cycle disorders. Mitchell S, Welch-Burke T, Dumitrescu L, Lomenick JP, Murdock DG, Crawford DC, Summar M. Mol Genet Metab. 2012 May;106(1):39-42. doi: 10.1016/j.ymgme.2012.02.011. Epub 2012 Feb 22.

Phase measurement of cognitive impairment specific to radiotherapy. Armstrong CL, Shera DM, Lustig RA, Phillips PC. Int J Radiat Oncol Biol Phys. 2012 Jul 1;83(3):e319-24. doi: 10.1016/j.ijrobp.2011.12.083. Epub 2012 Mar 13.

Prolonged hypoxia augments L-citrulline transport by system A in the newborn piglet pulmonary circulation. Fike CD, Sidoryk-Wegrzynowicz M, Aschner M, Summar M, Prince LS, Cunningham G, Kaplowitz M, Zhang Y, Aschner JL. Cardiovasc Res. 2012 Aug 1;95(3):375-84. doi: 10.1093/cvr/cvs186. Epub 2012 Jun 6.

Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders. Mokhtarani M, Diaz GA, Rhead W, Lichter-Konecki U, Bartley J, Feigenbaum A, Longo N, Berquist W, Berry SA, Gallagher R, Bartholomew D, Harding CO, Korson MS, McCandless SE, Smith W, Vockley J, Bart S, Kronn D, Zori R, Cederbaum S, Dorrani N, Merritt JL 2nd, Sreenath-Nagamani S, Summar M, Lemons C, Dickinson K, Coakley DF, Moors TL, Lee B, Scharschmidt BF. Mol Genet Metab. 2012 Nov;107(3):308-14. doi: 10.1016/j.ymgme.2012.08.006. Epub 2012 Aug 18.

Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate. Lichter-Konecki U, Diaz GA, Merritt JL 2nd, Feigenbaum A, Jomphe C, Marier JF, Beliveau M, Mauney J, Dickinson K, Martinez A, Mokhtarani M, Scharschmidt B, Rhead W. Mol Genet Metab. 2011 Aug;103(4):323-9. doi: 10.1016/j.ymgme.2011.04.013. Epub 2011 May 5.

Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported?. Jain-Ghai S, Nagamani SC, Blaser S, Siriwardena K, Feigenbaum A. Mol Genet Metab. 2011 Sep-Oct;104(1-2):107-11. doi: 10.1016/j.ymgme.2011.06.025. Epub 2011 Jul 13.

Argininosuccinate Lyase deficiency. *Sandesh C Sreenath Nagamani,  Ayelet Erez, Brendan Lee. (February 2011): in GeneReviews: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. Seattle (WA): University of Washington, Seattle, 1993-2011 Feb 03. Featured e-book on NCBI Bookshelf, Full Text.

Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond. Erez A, Nagamani SC, Lee B. Am J Med Genet C Semin Med Genet. 2011 Feb 15;157C(1):45-53. doi: 10.1002/ajmg.c.30289. Epub 2011 Feb 10.

Down-regulation of hepatic urea synthesis by oxypurines: xanthine and uric acid inhibit N-acetylglutamate synthase. Nissim I, Horyn O, Nissim I, Daikhin Y, Caldovic L, Barcelona B, Cervera J, Tuchman M, Yudkoff M. J Biol Chem. 2011 Jun 24;286(25):22055-68. doi: 10.1074/jbc.M110.209023. Epub 2011 May 3.

Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Ünalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; Nonalcoholic Steatohepatitis Clinical Research Network. JAMA. 2011 Apr 27;305(16):1659-68. doi: 10.1001/jama.2011.520.

Energy prediction equations are inadequate for obese Hispanic youth. Klein CJ, Villavicencio SA, Schweitzer A, Bethepu JS, Hoffman HJ, Mirza NM. J Am Diet Assoc. 2011 Aug;111(8):1204-10. doi: 10.1016/j.jada.2011.05.010.

Extracellular cyclophilin levels associate with parameters of asthma in phenotypic clusters. Stemmy EJ, Benton AS, Lerner J, Alcala S, Constant SL, Freishtat RJ. J Asthma. 2011 Dec;48(10):986-993. doi: 10.3109/02770903.2011.623334. Epub 2011 Oct 14.

Hepatitis B vaccination in HIV-infected youth: a randomized trial of three regimens. Flynn PM, Cunningham CK, Rudy B, Wilson CM, Kapogiannis B, Worrell C, Bethel J, Monte D, Bojan K; Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN). J Acquir Immune Defic Syndr. 2011 Apr;56(4):325-32. doi: 10.1097/QAI.0b013e318203e9f2.

Insights into the pathogenesis and treatment of cancer from inborn errors of metabolism. Erez A, Shchelochkov OA, Plon SE, Scaglia F, Lee B. Am J Hum Genet. 2011 Apr 8;88(4):402-21. doi: 10.1016/j.ajhg.2011.03.005.

Molecular characterization of CPS1 deletions by array CGH. Wang J, Shchelochkov OA, Zhan H, Li F, Chen LC, Brundage EK, Pursley AN, Schmitt ES, Häberle J, Wong LJ. Mol Genet Metab. 2011 Jan;102(1):103-6. doi: 10.1016/j.ymgme.2010.08.020. Epub 2010 Sep 19.

Molecular defects in human carbamoy phosphate synthetase I: mutational spectrum, diagnostic and protein structure considerations. Häberle J, Shchelochkov OA, Wang J, Katsonis P, Hall L, Reiss S, Eeds A, Willis A, Yadav M, Summar S; Urea Cycle Disorders Consortium, Lichtarge O, Rubio V, Wong LJ, Summar M. Hum Mutat. 2011 Jun;32(6):579-89. doi: 10.1002/humu.21406. Epub 2011 May 5.

N-acetylglutamate synthase deficiency: an insight into the genetics, epidemiology, pathophysiology, and treatment. Ah Mew N, Caldovic L. Appl Clin Genet. 2011 Aug 24;4:127-35. doi: 10.2147/TACG.S12702. Print 2011.

N-carbamylglutamate enhancement of ureagenesis leads to discovery of a novel deleterious mutation in a newly defined enhancer of the NAGS gene and to effective therapy. Heibel SK, Ah Mew N, Caldovic L, Daikhin Y, Yudkoff M, Tuchman M. Hum Mutat. 2011 Oct;32(10):1153-60. doi: 10.1002/humu.21553. Epub 2011 Sep 9.

New frontiers in neuroimaging applications to inborn errors of metabolism. Prust MJ, Gropman AL, Hauser N. Mol Genet Metab. 2011 Nov;104(3):195-205. doi: 10.1016/j.ymgme.2011.06.020. Epub 2011 Jun 30.

Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. Best BM, Capparelli EV, Diep H, Rossi SS, Farrell MJ, Williams E, Lee G, van den Anker JN, Rakhmanina N. J Acquir Immune Defic Syndr. 2011 Dec 1;58(4):385-91. doi: 10.1097/QAI.0b013e318232b057.

Phenylbutyrate improves nitrogen disposal via an alternative pathway without eliciting an increase in protein breakdown and catabolism in control and ornithine transcarbamylase-deficient patients. Marini JC, Lanpher BC, Scaglia F, O'Brien WE, Sun Q, Garlick PJ, Jahoor F, Lee B. Am J Clin Nutr. 2011 Jun;93(6):1248-54. doi: 10.3945/ajcn.110.009043. Epub 2011 Apr 13.

Phenylbutyrate therapy for maple syrup urine disease. Brunetti-Pierri N, Lanpher B, Erez A, Ananieva EA, Islam M, Marini JC, Sun Q, Yu C, Hegde M, Li J, Wynn RM, Chuang DT, Hutson S, Lee B. Hum Mol Genet. 2011 Feb 15;20(4):631-40. doi: 10.1093/hmg/ddq507. Epub 2010 Nov 23.

Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH, Gruchalla RS, Kattan M, Teach SJ, Pongracic JA, Chmiel JF, Steinbach SF, Calatroni A, Togias A, Thompson KM, Szefler SJ, Sorkness CA. N Engl J Med. 2011 Mar 17;364(11):1005-15. doi: 10.1056/NEJMoa1009705.

Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Nelson JE, Wilson L, Brunt EM, Yeh MM, Kleiner DE, Unalp-Arida A, Kowdley KV; Nonalcoholic Steatohepatitis Clinical Research Network. Hepatology. 2011 Feb;53(2):448-57. doi: 10.1002/hep.24038. Epub 2010 Nov 29.

Requirement of argininosuccinate lyase for systemic nitric oxide production. Erez A, Nagamani SC, Shchelochkov OA, Premkumar MH, Campeau PM, Chen Y, Garg HK, Li L, Mian A, Bertin TK, Black JO, Zeng H, Tang Y, Reddy AK, Summar M, O'Brien WE, Harrison DG, Mitch WE, Marini JC, Aschner JL, Bryan NS, Lee B. Nat Med. 2011 Nov 13;17(12):1619-26. doi: 10.1038/nm.2544.

Research challenges in central nervous system manifestations of inborn errors of metabolism. Dickson PI, Pariser AR, Groft SC, Ishihara RW, McNeil DE, Tagle D, Griebel DJ, Kaler SG, Mink JW, Shapiro EG, Bjoraker KJ, Krivitzky L, Provenzale JM, Gropman A, Orchard P, Raymond G, Cohen BH, Steiner RD, Goldkind SF, Nelson RM, Kakkis E, Patterson MC. Mol Genet Metab. 2011 Mar;102(3):326-38. doi: 10.1016/j.ymgme.2010.11.164. Epub 2010 Dec 2.

Vaccines are not associated with metabolic events in children with urea cycle disorders. Morgan TM, Schlegel C, Edwards KM, Welch-Burke T, Zhu Y, Sparks R, Summar M; Urea Cycle Disorders Consortium. Pediatrics. 2011 May;127(5):e1147-53. doi: 10.1542/peds.2010-1628. Epub 2011 Apr 11.

An exon 1 deletion in OTC identified using chromosomal microarray analyses in a mother and her two affected deceased newborns: implications for the prenatal diagnosis of ornithine transcarbamylase deficiency. Quintero-Rivera F,  Deignan J, Peredo J,  Grody W, Crandall B,  Sims M, Cederbaum S. Mol Genet Metab. 2010;101:413-416. PMID: 20817516, Full Text (with PubMed access).

Brain imaging in urea cycle disorders. Gropman A. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S20-30. doi: 10.1016/j.ymgme.2010.01.017. Epub 2010 Feb 13.

Diffusion tensor imaging detects areas of abnormal white matter microstructure in patients with partial ornithine transcarbamylase deficiency. Gropman AL, Gertz B, Shattuck K, Kahn IL, Seltzer R, Krivitsky L, Van Meter J. AJNR Am J Neuroradiol. 2010 Oct;31(9):1719-23. doi: 10.3174/ajnr.A2122. Epub 2010 May 20.

Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. Oldham MS, VanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Pediatr Neurol. 2010 Jan;42(1):49-52. doi: 10.1016/j.pediatrneurol.2009.07.017.

Early orthotopic liver transplantation in urea cycle defects: follow up of a developmental outcome study. Campeau PM, Pivalizza PJ, Miller G, McBride K, Karpen S, Goss J, Lee BH. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S84-7. doi: 10.1016/j.ymgme.2010.02.012. Epub 2010 Feb 19.

Epigenetics, copy number variation, and other molecular mechanisms underlying neurodevelopmental disabilities: new insights and diagnostic approaches. Gropman AL, Batshaw ML. J Dev Behav Pediatr. 2010 Sep;31(7):582-91. doi: 10.1097/DBP.0b013e3181ee384e.

Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium. Seminara J, Tuchman M, Krivitzky L, Krischer J, Lee HS, Lemons C, Baumgartner M, Cederbaum S, Diaz GA, Feigenbaum A, Gallagher RC, Harding CO, Kerr DS, Lanpher B, Lee B, Lichter-Konecki U, McCandless SE, Merritt JL, Oster-Granite ML, Seashore MR, Stricker T, Summar M, Waisbren S, Yudkoff M, Batshaw ML. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S97-105. doi: 10.1016/j.ymgme.2010.01.014. Epub 2010 Feb 10.

Guanidino compound levels in blood, cerebrospinal fluid, and postmortem brain material of patients with argininemia. Deignan JL, De Deyn PP, Cederbaum SD, Fuchshuber A, Roth B, Gsell W,  Marescau B. Mol Genet Metab. 2010;100 (suppl):S31-S36. PMID: 20176499, Full Text (with PubMed access).

Impaired generation of hepatitis B virus-specific memory B cells in HIV infected individuals following vaccination. Mehta N, Cunningham CK, Flynn P, Pepe J, Obaro S, Kapogiannis BG, Bethel J, Luzuriaga K; Adolescent Trials Network for HIV/AIDS Interventions. Vaccine. 2010 May 7;28(21):3672-8. doi: 10.1016/j.vaccine.2010.03.022. Epub 2010 Mar 28.

L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats. Vadivel A, Aschner JL, Rey-Parra GJ, Magarik J, Zeng H, Summar M, Eaton F, Thébaud B. Pediatr Res. 2010 Dec;68(6):519-25. doi: 10.1203/PDR.0b013e3181f90278.

Measuring in vivo ureagenesis with stable isotopes. Yudkoff M, Ah Mew N, Daikhin Y, Horyn O, Nissim I, Nissim I, Payan I, Tuchman M. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S37-41. doi: 10.1016/j.ymgme.2010.02.017. Epub 2010 Feb 26.

Milder clinical course of Type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70. *Shchelochkov OA, Li FY, Wang J, Zhan H, Towbin JA, Jefferies JL, Wong LJ, Scaglia F. Mol Genet Metab. 2010 OctNov;101(2-3):282-285. PMID: 20728387, Full Text (with PubMed access).

N-acetylglutamate synthase: structure, function and defects. Caldovic L, Ah Mew N, Shi D, Morizono H, Yudkoff M, Tuchman M. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S13-9. doi: 10.1016/j.ymgme.2010.02.018. Epub 2010 Feb 26.

N-carbamylglutamate augments ureagenesis and reduces ammonia and glutamine in propionic acidemia. Ah Mew N, McCarter R, Daikhin Y, Nissim I, Yudkoff M, Tuchman M. Pediatrics. 2010 Jul;126(1):e208-14. doi: 10.1542/peds.2010-0008. Epub 2010 Jun 21.

NeuroD6 genomic signature bridging neuronal differentiation to survival via the molecular chaperone network. Uittenbogaard M, Baxter KK, Chiaramello A. J Neurosci Res. 2010 Jan;88(1):33-54. doi: 10.1002/jnr.22182.

Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: safety, pharmacokinetics and ammonia control. Lee B, Rhead W, Diaz GA, Scharschmidt BF, Mian A, Shchelochkov O, Marier JF, Beliveau M, Mauney J, Dickinson K, Martinez A, Gargosky S, Mokhtarani M, Berry SA. Mol Genet Metab. 2010 Jul;100(3):221-8. doi: 10.1016/j.ymgme.2010.03.014. Epub 2010 Mar 23.

Randomized trial to determine safety and immunogenicity of two strategies for hepatitis B vaccination in healthy urban adolescents in the United States. Cunningham CK, Rudy BJ, Xu J, Bethel J, Kapogiannis BG, Ahmad S, Wilson CM, Flynn PM; Adolescent Medicine Trials Network for HIV/AIDS Interventions. Pediatr Infect Dis J. 2010 Jun;29(6):530-4. doi: 10.1097/INF.0b013e3181d285c7.

An automated communication system in a contact registry for persons with rare diseases: scalable tools for identifying and recruiting clinical research participants. Richesson RL, Lee HS, Cuthbertson D, Lloyd J, Young K, Krischer JP. Contemp Clin Trials. 2009 Jan;30(1):55-62. doi: 10.1016/j.cct.2008.09.002. Epub 2008 Sep 7.

Attention deficit/hyperactivity disorder symptoms moderate cognition and behavior in children with autism spectrum disorders. Yerys BE, Wallace GL, Sokoloff JL, Shook DA, James JD, Kenworthy L. Autism Res. 2009 Dec;2(6):322-33. doi: 10.1002/aur.103.

Clinical research for rare disease: opportunities, challenges, and solutions. Griggs RC, Batshaw M, Dunkle M, Gopal-Srivastava R, Kaye E, Krischer J, Nguyen T, Paulus K, Merkel PA; Rare Diseases Clinical Research Network. Mol Genet Metab. 2009 Jan;96(1):20-6. doi: 10.1016/j.ymgme.2008.10.003. Epub 2008 Nov 13.

Effects of a single dose of N-carbamylglutamate on the rate of ureagenesis. Ah Mew N, Payan I, Daikhin Y, Nissim I, Nissim I, Tuchman M, Yudkoff M. Mol Genet Metab. 2009 Dec;98(4):325-30. doi: 10.1016/j.ymgme.2009.07.010. Epub 2009 Jul 14.

Expression profiling of inflammatory mediators in pediatric sinus mucosa. Wu X, Ghimbovschi S, Aujla PK, Rose MC, Peña MT. Arch Otolaryngol Head Neck Surg. 2009 Jan;135(1):65-72. doi: 10.1001/archoto.2008.505.

Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases. Mitchell S, Ellingson C, Coyne T, Hall L, Neill M, Christian N, Higham C, Dobrowolski SF, Tuchman M, Summar M; Urea Cycle Disorder Consortium. Hum Mutat. 2009 Jan;30(1):56-60. doi: 10.1002/humu.20813.

High-frequency detection of deletions and variable rearrangements at the ornithine transcarbamylase (OTC) locus by oligonucleotide Array CGH. Shchelochkov OA, Li F, Geraghty MT, Gallagher RC, Van Hove JL, Lichter-Konecki U, Fernhoff PM, Copeland S, Reimschisel,T, Cederbaum S, Lee B, Chinault AC, Wong L. Mol Genet Metab. 2009;96: 97-105. PMID: 19138872, Full Text (with PubMed access).

Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Krivitzky L, Babikian T, Lee HS, Thomas NH, Burk-Paull KL, Batshaw ML. Pediatr Res. 2009 Jul;66(1):96-101. doi: 10.1203/PDR.0b013e3181a27a16.

Ornithine transcarbamylase deficiency with persistent abnormality in cerebral glutamate metabolism in adults. Gropman AL, Sailasuta N, Harris KC, Abulseoud O, Ross BD. Radiology. 2009 Sep;252(3):833-41. doi: 10.1148/radiol.2523081878. Epub 2009 Jun 30.

Ornithine transcarbamylase deficiency: a possible risk factor for thrombosis. Venkateswaran L, Scaglia F, McLin V, Hertel P, Shchelochkov OA, Karpen S, Mahoney D Jr, Yee DL. Pediatr Blood Cancer. 2009 Jul;53(1):100-2. doi: 10.1002/pbc.22016.

Profiling of oxidative stress in patients with inborn errors of metabolism. Mc Guire PJ, Parikh A, Diaz GA. Mol Genet Metab. 2009 Sep-Oct;98(1-2):173-180. PMID: 19604711, PMCID: PMC2915835.

Quantitative RT-PCR comparison of the urea and nitric oxide cycle gene transcripts in adult human tissues. Neill MA, Aschner J, Barr F, Summar ML. Mol Genet Metab. 2009 Jun;97(2):121-7. doi: 10.1016/j.ymgme.2009.02.009. Epub 2009 Mar 3.

Systemic hypertension in two patients with ASL deficiency: a result of nitric oxide deficiency?. Brunetti-Pierri N, Erez A, Shchelochkov O, Craigen W, Lee B. Mol Genet Metab. 2009 Sep-Oct;98(1-2):195-7. doi: 10.1016/j.ymgme.2009.06.006. Epub 2009 Jun 13.

1H MRS allows brain phenotype differentiation in sisters with late onset ornithine transcarbamylase deficiency (OTCD) and discordant clinical presentations. Gropman AL, Seltzer RR, Yudkoff M, Sawyer A, VanMeter J, Fricke ST. Mol Genet Metab. 2008 May;94(1):52-60. doi: 10.1016/j.ymgme.2007.12.008. Epub 2008 Feb 11.

1H MRS identifies symptomatic and asymptomatic subjects with partial ornithine transcarbamylase deficiency. Gropman AL, Fricke ST, Seltzer RR, Hailu A, Adeyemo A, Sawyer A, van Meter J, Gaillard WD, McCarter R, Tuchman M, Batshaw M; Urea Cycle Disorders Consortium. Mol Genet Metab. 2008 Sep-Oct;95(1-2):21-30. doi: 10.1016/j.ymgme.2008.06.003. Epub 2008 Jul 26.

3-isobutylmethylxanthine inhibits hepatic urea synthesis: protection by agmatine. Nissim I, Horyn O, Nissim I, Daikhin Y, Wehrli SL, Yudkoff M. J Biol Chem. 2008 May 30;283(22):15063-71. doi: 10.1074/jbc.M800163200. Epub 2008 Mar 28.

A ground truth based comparative study on clustering of gene expression data. Zhu Y, Wang Z, Miller DJ, Clarke R, Xuan J, Hoffman EP, Wang Y. Front Biosci. 2008 May 1;13:3839-49. doi: 10.2741/2972.

Clinical NOE 13C MRS for neuropsychiatric disorders of the frontal lobe. Sailasuta N, Robertson LW, Harris KC, Gropman AL, Allen PS, Ross BD. J Magn Reson. 2008 Dec;195(2):219-25. doi: 10.1016/j.jmr.2008.09.012. Epub 2008 Sep 17.

Complex management of a patient with a contiguous Xp11.4 gene deletion involving ornithine transcarbamylase: a role for detailed molecular analysis in complex presentations of classical diseases. Deardorff MA, Gaddipati H, Kaplan P, Sanchez-Lara PA, Sondheimer N, Spinner NB, Hakonarson H, Ficicioglu C, Ganesh J, Markello T, Loechelt B, Zand DJ, Yudkoff M, Lichter-Konecki U. Mol Genet Metab. 2008 Aug;94(4):498-502. doi: 10.1016/j.ymgme.2008.04.011. Epub 2008 Jun 3.

Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Tuchman M, Lee B, Lichter-Konecki U, Summar ML, Yudkoff M, Cederbaum SD, Kerr DS, Diaz GA, Seashore MR, Lee HS, McCarter RJ, Krischer JP, Batshaw ML; Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. Mol Genet Metab. 2008 Aug;94(4):397-402. doi: 10.1016/j.ymgme.2008.05.004. Epub 2008 Jun 17.

Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Summar ML, Dobbelaere D, Brusilow S, Lee B. Acta Paediatr. 2008 Oct;97(10):1420-5. doi: 10.1111/j.1651-2227.2008.00952.x. Epub 2008 Jul 17.

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. Lichter-Konecki U, Mangin JM, Gordish-Dressman H, Hoffman EP, Gallo V. Glia. 2008 Mar;56(4):365-77. doi: 10.1002/glia.20624.

N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers. Tuchman M, Caldovic L, Daikhin Y, Horyn O, Nissim I, Nissim I, Korson M, Burton B, Yudkoff M. Pediatr Res. 2008 Aug;64(2):213-7. doi: 10.1203/PDR.0b013e318179454b.

Neurometabolic disorders: urea-cycle disorder, outcomes, development and treatment. *Gropman AL, Rigas A. Pediatric Health. 2008;2(6):701-713. Full Text.

Phenotypic correction of ornithine transcarbamylase deficiency using low dose helper-dependent adenoviral vectors. Brunetti-Pierri N, Clarke C, Mane V, Palmer DJ, Lanpher B, Sun Q, O'Brien W, Lee B. J Gene Med. 2008 Aug;10(8):890-896. PMID: 18563850, PMCID: PMC2766563.

Profiling of astrocyte properties in the hyperammonaemic brain: shedding new light on the pathophysiology of the brain damage in hyperammonaemia. Lichter-Konecki U. J Inherit Metab Dis. 2008 Aug;31(4):492-502. doi: 10.1007/s10545-008-0834-9. Epub 2008 Aug 9.

Recommendations for locusspecific databases and their curation. Cotton RG, Auerbach AD, Beckmann JS, Blumenfeld OO, Brookes AJ, Brown AF, Carrera P, Cox DW, Gottlieb B, Greenblatt MS, Hilbert P, Lehvaslaiho H, Liang P, Marsh S, Nebert DW, Povey S, Rossetti S, Scriver CR, Summar M, Tolan DR, Verma IC, Vihinen M, den Dunnen JT. Hum Mutat. 2008;29(1):2-5. PMID: 18157828, PMCID: PMC2752432.

SNOMED CT coding variation and grouping for "other findings" in a longitudinal study on urea cycle disorders. Patrick TB, Richesson R, Andrews JE, Folk LC. AMIA Annu Symp Proc. 2008 Nov 6;2008:11-5.

The role of molecular testing and enzyme analysis in the management of hypomorphic citrullinemia. Dimmock DP, Trapane P, Feigenbaum A, Keegan CE, Thoene J, Cederbaum S, Gibson J, Gambello M, Muenzer J, Vaux K, O'Brien WO, Fang P. Dimmock DP, Trapane P, Feigenbaum A, Keegan CE, Thoene J, Cederbaum S, Gibson J, Gambello M, Muenzer J, Vaux K, O'Brien WO, Fang P. The role of molecular testing and enzyme analysis in the management of hypomorphic citrullinemia. Am J Med Genet A. 2008 Nov 15; 146A(22): 2885–2890. PMID: 18925679, PMCID: PMC2597641

Assessing the functional characteristics of synonymous and nonsynonymous mutation candidates by use of large DNA constructs. Eeds AM, Mortlock D, Wade-Martins R, Summar ML. Am J Hum Genet. 2007 Apr;80(4):740-50. doi: 10.1086/513287. Epub 2007 Mar 8.

Citrin deficiency: A novel cause of failure to thrive that responds to a high protein, low carbohydrate diet. Dimmock DP, Kobayashi K, Iijima M, Tabata A, Wong LJ, Lee B, Saheki T, Scaglia F. Pediatrics. 2007;119:e773-e777. PMID: 17332192, Full Text (with PubMed access).

Mutations and polymorphisms in the human N-acetylglutamate synthase gene. Caldovic L, Morizono H, Tuchman M. Hum Mutat. 2007;28:754-759. PMID: 17421020, Full Text.

Neurological implications of urea cycle disorders. Gropman AL, Summar M, Leonard JV. J Inherit Metab Dis. 2007 Nov;30(6):865-79. doi: 10.1007/s10545-007-0709-5. Epub 2007 Nov 23.

Phenylbutyrate reduces plasma leucine concentrations without affecting the flux of leucine. *Marini JC, Lanpher B, Scaglia F, Carter S, Garlick PJ, Jahoor F, Lee B. FASEB Journal. 2007;21:A335. Abstract.

Role of branched chain amino acids in patients with urea cycle disorders. *Scaglia F, Lanpher B, Marini J, Lee B. In: Bachmann C, Haberle J, Leonard JV (eds). Pathophysiology and Management of Hyperammonemia. SPS Publications, 2007: p.65-75. 

Streamlined assessment of gene variants by high resolution melt profiling utilizing the ornithine transcarbamylase gene as a model system. Dobrowolski SF, Ellingson C, Caldovic L, Tuchman M. Hum Mutat. 2007;28:1133-1140. PMID: 17565723.

The ketogenic diet and brain metabolism of amino acids: relationship to the anticonvulsant effect. Yudkoff M, Daikhin Y, Melø TM, Nissim I, Sonnewald U, Nissim I. Annu Rev Nutr. 2007;27:415-30. doi: 10.1146/annurev.nutr.27.061406.093722.

Urea cycle disorders. *EA Crombez, SD Cederbaum. In: Schapira AHV (ed) Neurology and Clinical Neuroscience. Mosby 2007, chapter 110, pp1469-1476.

Clinical and functional characterization of a human ORNT1mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Camacho JA, Mardach MR, Rioseco-Camacho N, Ruiz-Pesini E, Derbeneva O, Andrade D, Zaldivar F, Qu Y, Cederbaum SD. Pediatr Res. 2006;60:423-429. PMID: 16940241, Full Text.

Inborn errors of metabolism: the flux from Mendelian to complex diseases. Lanpher B, Brunetti-Pierri N, Lee B. Nat Rev Genet. 2006 Jun;7(6):449-60. doi: 10.1038/nrg1880.

Mutations and polymorphisms in the human ornithine transcarbamylase gene. Yamaguchi S, Brailey LL, Morizono H, Lynch MG, Bale AE, Tuchman M. Hum Mutat. 2006;27:626-632. PMID: 11793468, Full Text.

The frequent observation of evidence for nonsense-mediated decay in RNA from patients with carbamyl phosphate synthetase I deficiency. Eeds AM, Hall LD, Yadav M, Willis A, Summar S, Putnam A, Barr F, Summar ML. Mol Genet Metab. 2006 Sep-Oct;89(1-2):80-6. doi: 10.1016/j.ymgme.2006.04.006. Epub 2006 Jun 5.

Considerations in the difficult-to-manage urea cycle disorder patient. Lee B, Singh RH, Rhead WJ, Sniderman King L, Smith W, Summar ML. Crit Care Clin. 2005 Oct;21(4 Suppl):S19-25. doi: 10.1016/j.ccc.2005.05.001.

Genetic counseling issues in urea cycle disorders. Sniderman King L, Singh RH, Rhead WJ, Smith W, Lee B, Summar ML. Crit Care Clin. 2005 Oct;21(4 Suppl):S37-44. doi: 10.1016/j.ccc.2005.08.001.

Hyperargininemia due to liver arginase deficiency. Crombez EA, Cederbaum SD. Mol Genet Metab. 2005 Mar;84(3):243-51. doi: 10.1016/j.ymgme.2004.11.004. Epub 2004 Dec 19.

Management and outcome of neonatal-onset ornithine transcarbamylase deficiency following liver transplantation at 60 days of life. Ensenauer R, Tuchman M, El-Youssef M, Kotagal S, Ishitani MB, Matern D, Babovic-Vuksanovic D. Mol Genet Metab. 2005;84:363-366 PMID: 15781198, Full Text (with PubMed access).

Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS clinical trials group study. Hulgan T, Haas DW, Haines JL, Ritchie MD, Robbins GK, Shafer RW, Clifford DB, Kallianpur AR, Summar M, Canter JA. AIDS. 2005 Sep 2;19(13):1341-9. doi: 10.1097/01.aids.0000180786.02930.a1.

Nutritional management of urea cycle disorders. Singh RH, Rhead WJ, Smith W, Lee B, Sniderman King L, Summar M. Crit Care Clin. 2005 Oct;21(4 Suppl):S27-35. doi: 10.1016/j.ccc.2005.08.003.

Unmasked adult-onset urea cycle disorders in the critical care setting. Summar ML, Barr F, Dawling S, Smith W, Lee B, Singh RH, Rhead WJ, Sniderman King L, Christman BW. Crit Care Clin. 2005 Oct;21(4 Suppl):S1-8. doi: 10.1016/j.ccc.2005.05.002.

Urea cycle disorders: clinical presentation outside the newborn period. Smith W, Kishnani PS, Lee B, Singh RH, Rhead WJ, Sniderman King L, Smith M, Summar M. Crit Care Clin. 2005 Oct;21(4 Suppl):S9-17. doi: 10.1016/j.ccc.2005.05.007.

Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. Scaglia F, Brunetti-Pierri N, Kleppe S, Marini J, Carter S, Garlick P, Jahoor F, O'Brien W, Lee B. J Nutr. 2004 Oct;134(10 Suppl):2775S-2782S; discussion 2796S-2797S. doi: 10.1093/jn/134.10.2775S.

Cognitive outcome in urea cycle disorders. Gropman AL, Batshaw ML. Mol Genet Metab. 2004 Apr;81 Suppl 1:S58-62. doi: 10.1016/j.ymgme.2003.11.016.

Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients. Scaglia F, Carter S, O’Brien W, Lee B. Mol Genet Metab. 2004;81S:79-85. PMID: 15050979, Full Text (with PubMed access).

Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I. Summar ML, Hall LD, Christman B, Barr F, Smith H, Kallianpur A, Brown N, Yadav M, Willis A, Eeds A, Cermak E, Summar S, Wilson A, Arvin M, Putnam A, Wills M, Cunningham G. Mol Genet Metab. 2004;81(Suppl 1):S12-S19. PMID: 15050969, Full Text (with PubMed access).

Fatal presentation of ornithine transcarbamylase deficiency in a 62-year-old man and family studies. Rohininath T, Costello DJ, Lynch T, Monavari A, Tuchman M, Treacy EP. J Inherit Metab Dis. 2004;27:285-288. PMID: 15243986.

Hyperammonemia: are the burdens too grave? Case study. Tuchman M. Ethics Intellect Disabil. 2004;8:1,3. PMID: 15835081.

Long-term correction of ornithine transcarbamylase deficiency by WPRE-mediated overexpression using a helper-dependent adenovirus. Mian A, McCormack WM Jr, Mane V, Kleppe S, Ng P, Finegold M, O'Brien WE, Rodgers JR, Beaudet AL, Lee B. Mol Ther. 2004 Sep;10(3):492-9. doi: 10.1016/j.ymthe.2004.05.036.

New secondary metabolites of phenylbutyrate in humans and rats. Kasumov T, Brunengraber LL, Comte B, Puchowicz MA, Jobbins K, Thomas K, David F, Kinman R, Wehrli S, Dahms W, Kerr D, Nissim I, Brunengraber H. Drug Metab Dispos. 2004;32:10-19. PMID: 14709615, Full Text.

Pharmacokinetics of sodium phenylacetate and sodium benzoate following intravenous administration as both a bolus and continuous infusion to healthy adult volunteers. MacArthur RB, Altincatal A, Tuchman M. Mol Genet Metab. 2004;Suppl:67-73. PMID: 15050977, Full Text (with PubMed access).

Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate. Caldovic L, Morizono H, Daikhin Y, Nissim I, McCarter RJ, Yudkoff M, Tuchman M. J Pediatr. 2004 Oct;145(4):552-4. doi: 10.1016/j.jpeds.2004.06.047.

Urea cycle disorders workshop introduction. Tuchman M. Mol Genet Metab. 2004;81(Suppl):3. Full Text.

Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders. Takanashi JI, Barkovich AJ, Cheng SF, Weisiger K, Zlatunich CO, Mudge C, Rosenthal P, Tuchman M, Packman S. Am J Neuroradiol. 2003;24:1184-1187. PMID: 12812952, Full Text.

Characterization of genomic structure and polymorphisms in the human carbamyl phosphate synthetase I gene. Summar ML, Hall LD, Eeds AM, Hutcheson HB, Kuo AN, Willis AS, Rubio V, Arvin MK, Schofield JP, Dawson EP. Gene. 2003;311:51-57. PMID: 12853138, Full Text (with PubMed access).

Differential utilization of systemic and enteral ammonia for urea synthesis in control subjects and carriers for ornithine transcarbamylase deficiency. Scaglia F, Rosenberger J, Henry J, Lee B, Reeds P. Am J Clin Nutr. 2003;78:749-755. PMID: 14522733, Full Text.

Effect of cardiopulmonary bypass on urea cycle intermediates and nitric oxide levels after congenital heart surgery. Barr FE, Beverley H, VanHook K, Cermak E, Christian K, Drinkwater D, Dyer K, Raggio NT, Moore JH, Christman B, Summar M. J Pediatr. 2003;142(1):26-30. PMID: 12520250, Full Text (with PubMed access).

Null mutations in the Nacetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Caldovic L, Morizono M, Panglao M, Cheng SF, Packman S, Tuchman M. Hum Genet. 2003;112:364-368. PMID: 12594532, Full Text (with PubMed access).

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