Partial Ornithine Transcarbamylase Research Articles

Variable disease manifestations and metabolic management within a single family affected by ornithine transcarbamylase deficiency

We report on a family with ornithine transcarbamylase (OTC) deficiency, an X-linked urea cycle disorder, with variable disease severity and tailored management strategies based on each family member's biochemical profile and clinical presentation. Our primary patient is a female monozygotic twin who presented to medical care at 10 months of age with acute liver failure, gastrointestinal symptoms, altered mental status, hypoglycemia, and hyperammonemia. The patient's older brother, known to have hemizygous OTC deficiency, died at 8 months of age from cardiac arrest after complications secondary to his diagnosis. Despite her family history, manifestation of symptoms of heterozygous (partial) OTC deficiency went unrecognized by multiple providers based on misconceptions regarding a female's risk for X-linked disease. Despite barriers related to the family's low socioeconomic status, follow-up care by a multidisciplinary metabolic care team, including moderate protein restriction and nitrogen scavenger therapy, led to positive outcomes for the patient. Her twin sister and mother are also heterozygous for variants in OTC and remain controlled on moderate protein restriction. This case illustrates the importance of genotyping all individuals with genetic risk factors for OTC deficiency and the variability in disease manifestation that necessitates tailored treatment approaches for individuals with partial OTC deficiency.

HYPERAMMONEMIC COMA IN A PATIENT WITH ORNITHINE TRANSCARBAMYLASE DEFICIENCY

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Ornithine transcarbamylase (OTC) deficiency is a rare, X-linked inherited disorder of the urea cycle affecting 1 in 80,000 live births. It is characterized by the inability to break down nitrogen to urea. The resulting hyperammonemia leads to lethargy, hypotonia, seizures and developmental delay if the illness manifests in infancy, and migraines, ataxia, hyperammonemic coma in adults. Early recognition and treatment of hyperammonemia is the key to prevent neurological disability in infancy and hyperammonemic coma leading to death in adults. CASE PRESENTATION: 46-year-old female with past medical history of partial OTC deficiency and complex partial seizures presented to the hospital with chief complaint of altered mental status. In the emergency department, vitals were remarkable for tachycardia. Exam was significant for altered mental status and a Glasgow Coma Scale of 8. Initial labs were significant for hyperammonemia (234 mcmol/L), hypernatremia (160 mmol/L) and abnormal urinary analysis with signs of infection. Patient was admitted to the intensive care unit followed by initiation of lactulose and rifaximin for treatment of hyperammonemia. She was also started on broad spectrum antibiotics for suspicion of urinary tract infection. Electrolyte abnormalities were gradually corrected. However, her condition kept on deteriorating to the point that she was not responding to verbal, tactile or painful stimuli. She was subsequently intubated on the second day of hospitalization due to failure to protect airway. Serial ammonia levels were monitored that kept on increasing. Electroencephalogram showed severe metabolic encephalopathy without seizures. Computerized tomography scan of the brain did not show acute intracranial process. At this point, nephrology was consulted, and patient underwent continuous renal replacement therapy with dramatic improvement of serum ammonia level and her neurological status. This was followed by successful extubation and a gradual return to baseline mental status. She was continued on lactulose, rifaximin and advised to remain on low protein diet. DISCUSSION: This case highlights the rare complication of hyperammonemic coma in an adult patient with history of OTC deficiency. It is an X-linked defect with variable onset and presentation depending on the sex and activity of the enzyme. Patients classically present with lethargy, seizures and hyperammonemia leading to metabolic encephalopathy, coma and death. Diagnosis involves serum amino acid quantitative analysis and urinary orotic acid concentration in urine. Low serum citrulline and elevated urinary orotic acid levels confirm the OTC deficiency. DNA sequencing-based mutation analysis can also be used as first line for diagnosis. Treatment involves rapidly decreasing serum ammonia with lactulose, rifaximin or dialysis. Prognosis depends on the age of presentation and duration of hyperammonemia. CONCLUSIONS: XXX. REFERENCE #1: Summar, Marshall. "Current strategies for the management of neonatal urea cycle disorders." The Journal of pediatrics 138, no. 1 (2001): S30-S39. DISCLOSURES: No relevant relationships by Fatima Ayub, source=Web Response No relevant relationships by Muhammad Hasib Khalil, source=Web Response

Ornithine Transcarbamylase Deficiency Presenting with Symptoms of Mania in a Young Adult Male

The purpose of this case study is to review the clinical presentation and medical workup of a young adult male presenting with acute behavior changes in the setting of undiagnosed ornithine transcarbamylase deficiency (OTCD). This case study involves a 19-year-old male with a psychiatric history of depression and one previous suicide attempt, who presented to a large midwestern university hospital emergency department after being found by police naked in a neighbor's yard. He displayed manic signs and symptoms, including euphoria, lack of sleep for five days, and attempting to purchase a new car and three large screen TVs. Family reported the patient uncharacteristically announced three weeks earlier that he was vegetarian and stopped eating his frequent customary cheeseburgers. Due to increased anxiety and inability to sleep, the patient received lorazepam 2 mg in the emergency department. Upon transfer to the psychiatric unit, therapy was initiated with aripiprazole 5 mg daily and valproate 1000 mg nightly on Day 1 of treatment. The patient refused medications on hospital Day 2, then received this combination again on Day 3. The next morning, the patient complained of lethargy, headache, nausea, and vomiting. The patient's ammonia level was found to be 204 micromol/L with ALT and AST of 714 and 647 IU/L respectively. Tests for infectious hepatitis were negative. Medical consultation recommended discontinuation of current medications, vigorous hydration, and further work up. On further investigation, the patient was found to have low plasma citrulline level of 8 micromol/L, undetectable plasma arginine, and high urinary orotic acid. The laboratory data showed a biochemical phenotype consistent with a diagnosis of partial OTCD, an X-linked urea cycle disorder resulting in toxic hyperammonemia. The patient was treated with a low protein diet modification as well as a combination of sodium benzoate and sodium phenylbutyrate to reduce serum ammonia concentration. With treatment the patient's laboratory values normalized, and mental status improved. In conclusion, partial ornithine transcarbamylase deficiency may manifest with psychiatric symptoms in early adulthood. In young patients with elevated ammonia and mental status change, OTCD is an important diagnosis to consider, as it is the most common inherited cause of hyperammonemia.

Undiagnosed Partial Ornithine Transcarbamylase Deficiency Presenting Postoperatively as Agitated Delirium.

Partial ornithine transcarbamylase deficiency (pOTCD), an enzymatic defect within the urea cycle, is an increasingly recognized etiology for hyperammonemia of unclear source following a stressor within female adults. Here we present a case of newly diagnosed pOTCD following a systemic stressor and prolonged hospitalization course. From a neurological perspective, prompt recognition provided the patient with a swift and near complete recovery. We briefly review the pertinent literature pertaining to this genetically based condition including historical context and current therapeutic approaches. Given the potential morbidity of prolonged hyperammonemia, neurohospitalists need to be aware of partial ornithine transcarbamylase as an entity.

Valproate-induced hyperammonemic coma in females with unrecognized partial ornithine transcarbamylase deficiency

A female child with undiagnosed partial ornithine transcarbamylase deficiency suffered hyperammonemic coma after initiation of valproate for suspected seizures. Retrospec tive history and metabolic testing indicated ornithine tra nscarbamylase deficiency. This case, along with previous reports in childr en and adults, demonstrates the importance of a focused history and consideration of appropriate metabolic testing prior to im plementation of valproate therapy especially in female patients.

Diffusion tensor imaging detects areas of abnormal white matter microstructure in patients with partial ornithine transcarbamylase deficiency.

OTCD, an X-linked disorder, is the most common of the UCDs. Neonatal onset is associated with uniformly poor outcome. Males with late-onset OTCD show deficits in executive function, motor planning, and working memory. A broad phenotype is observed in heterozygous females. A specific neurobehavioral phenotype with white matter dysfunction and impaired attention and working memory has been described. The extent to which the deficits involve specific pathways in the brain is unknown. We hypothesized that DTI would disclose white matter microstructure in OTCD correlating with cognitive deficits. Nineteen adults with partial OTCD and 18 adult control subjects ages 19-59 years participated. MR imaging was performed by using a 3T whole-body scanner. Anisotropy was calculated from the eigenvalues of the diffusion tensor by using the FA metric and was compared between the study and control groups. FA of the frontal white matter was significantly decreased in subjects, indicating changes in white matter microstructure. There was an inverse relationship between FA and disease severity, but not with age. Findings of MR imaging in OTCD are often normal in patients with late-onset disease, heterozygotes, or in those not in hyperammonemic crisis. DTI was more sensitive than FSE T2-weighted imaging for detecting abnormalities in normal-appearing white matter. The extent of abnormality correlated with cognitive deficits. The location of the deficits in the frontal white matter is important because this area connects fibers that are vital to executive function, attention, and working memory.

Abstract #2: Adults with Ornithine Transcarbamylase Deficiency (OTCD) Demonstrate Persistent Abnormality in Cerebral Glutamate Metabolism

Objective 13C MRS to determine cerebral glutamate turnover rate in partial ornithine transcarbamylase deficiency (OTCD). Background Patients with OTCD manifest neuropsychological disorders. Proton magnetic resonance spectroscopy (1H MRS) demonstrates neurochemical abnormalities in OTCD similar to chronic and subclinical hepatic encephalopathy (SCHE) in whom impaired cerebral glucose metabolism and reduced glutamine-glutamate cycling or glutamate neurotransmission rate (GNT) have been observed. We hypothesize impaired GNT may underlie cognitive deficits in OTCD. Design/Methods MRI, 1H MRS and 13C MRS were performed on a clinical GE 1.5 T MR scanner in 6 patients with OTCD and 4 normal controls, imaged in stable condition. Each received i.v. 13C glucose (0.2 g/kg) C1 or C2, as a 15-min bolus. Cerebral metabolites were determined with proton decoupling, in posterior cingulate gyrus (PCG, N = 9) and without proton decoupling, in anterior (N = 1) cingulate gyrus (ACG) over 60–100 minutes. Results 1. Uptake and removal of cerebral glucose (13C-C1 or C2) were comparable in normal controls and subjects with OTCD ( p > 0.1). 2. Glucose C1 was metabolized to glutamate C4 and glucose C2 to glutamate C5 at comparable rates which were significantly reduced in OTCD (combined p p > 0.1). 4. 13C - 2 glucose and its metabolic products were observed in ACG without proton decoupling in a single subject with OTCD. Conclusions/Relevance Reduced GNT secondary to impaired cerebral glucose metabolism was documented in OTCD using 13C MRS of occipital lobe. Feasibility of this measurement in more relevant frontal brain structures was demonstrated. Treatment(s) which improve cerebral glucose metabolism and GNT may improve neurological outcome in OTCD where prevention and treatment of hyperammonemic episodes appears insufficient.

Ornithine Transcarbamylase Deficiency with Persistent Abnormality in Cerebral Glutamate Metabolism in Adults

To determine cerebral glutamate turnover rate in partial-ornithine transcarbamylase deficiency (OTCD) patients by using carbon 13 ((13)C) magnetic resonance (MR) spectroscopy. The study was performed with approval of the institutional review board, in compliance with HIPAA regulations, and with written informed consent of the subjects. MR imaging, hydrogen 1 ((1)H) MR spectroscopy, and (13)C MR spectroscopy were performed at 1.5 T in 10 subjects, six patients with OTCD and four healthy control subjects, who were in stable condition. Each received intravenous (13)C-glucose (0.2 g/kg), C1 or C2 position, as a 15-minute bolus. Cerebral metabolites were determined with proton decoupling in a parieto-occipital region (n = 9) and without proton decoupling in a frontal region (n = 1) during 60-120 minutes. Uptake and removal of cerebral glucose ([1-(13)C]-glucose or [2-(13)C]-glucose) were comparable in healthy control subjects and subjects with OTCD (P = .1). Glucose C1 was metabolized to glutamate C4 and glucose C2 was metabolized to glutamate C5 at comparable rates, both of which were significantly reduced in OTCD (combined, P = .04). No significant differences in glutamine formation were found in subjects with OTCD (P = .1). [2-(13)C]-glucose and its metabolic products were observed in anterior cingulate gyrus without proton decoupling in one subject with OTCD. Treatments that improve cerebral glucose metabolism and glutamate neurotransmission may improve neurologic outcome in patients with OTCD, in whom prevention and treatment of hyperammonemic episodes appear to be insufficient.

1H MRS identifies symptomatic and asymptomatic subjects with partial ornithine transcarbamylase deficiency

Objective: To evaluate brain metabolism in subjects with partial ornithine transcarbamylase deficiency (OTCD) utilizing 1H MRS. Methods: Single-voxel 1H MRS was performed on 25 medically-stable adults with partial OTCD, and 22 similarly aged controls. Metabolite concentrations from frontal and parietal white matter (FWM, PWM), frontal gray matter (FGM), posterior cingulate gray matter (PCGM), and thalamus (tha) were compared with controls and IQ, plasma ammonia, glutamine, and disease severity. Results: Cases ranged from 19 to 59 years; average 34 years; controls ranged from 18 to 59 years; average 33 years. IQ scores were lower in cases (full scale 111 vs. 126; performance IQ 106 vs. 117). Decreased myoinositol (mI) in FWM ( p = 0.005), PWM ( p < 0.001), PCGM ( p = 0.003), and tha ( p = 0.004), identified subjects with OTCD, including asymptomatic heterozygotes. Glutamine (gln) was increased in FWM ( p < 0.001), PWM ( p < 0.001), FGM ( p = 0.002), and PCGM ( p = 0.001). Disease severity was inversely correlated with [mI] in PWM ( r = −0.403; p = 0.046) and directly correlated with [gln] in PCGM ( r = 0.548; p = 0.005). N-Acetylaspartate (NAA) was elevated in PWM ( p = 0.002); choline was decreased in FWM ( p = 0.001) and tha ( p = 0.002). There was an inverse relationship between [mI] and [gln] in cases only. Total buffering capacity (measured by [mI/mI + gln] ratio, a measure of total osmolar capacity) was inversely correlated with disease severity in FWM ( r = −0.479; p = 0.018), PWM ( r = −0.458; p = 0.021), PCGM ( r = −0.567; p = 0.003), and tha ( r = −0.345; p = 0.037). Conclusion: Brain metabolism is impaired in partial OTCD. Depletion of mI and total buffering capacity are inversely correlated with disease severity, and serve as biomarkers.

Hemodialysis for hyperammonemia associated with ornithine transcarbamylase deficiency

Acute hyperammonemia is a medical emergency requiring rapid recognition and treatment to prevent devastating neurologic sequelae. Its varying etiologies include primary hepatic failure, drug toxicity, infection, and inherited disorders of metabolism. Ornithine transcarbamylase (OTC) deficiency is the most common inherited urea cycle disorder and can result in hyperammonemic encephalopathy and coma, often presenting in the newborn or early childhood. Partial deficiencies of the enzyme can present later in adulthood with protean neuropsychiatric signs and symptoms. Early recognition and management of metabolic encephalopathy is crucial to avoid neurologic damage, and may require hemodialysis for rapid removal of ammonia, with adjunctive medications and dietary modifications to decrease endogenous nitrogen production and activate alternate pathways of nitrogen excretion. We present the case of an adult patient with partial OTC deficiency who presented with encephalopathy, coma, and seizures, accompanied by hyperammonemia and treated acutely with hemodialysis.

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

A male infant was diagnosed prenatally with a partial ornithine transcarbamylase ( OTC) gene deletion and managed from birth. However, he displayed neurological abnormalities and developed pleural effusions, ascites and anasarca not solely explained by OTC deficiency (OTCD). Further evaluation of the gene locus using exon-specific PCR and high-density SNP array copy number analysis revealed a 3.9-Mb deletion from Xp11.4 to Xp21.1 including five additional gene deletions, three causing the known genetic diseases: Retinitis pigmentosa (RP3), X-linked chronic granulomatous disease (CGD) and McLeod syndrome. The case illustrates (1) the complexities of managing a patient with neonatal onset OTCD, CGD, RP3 and McLeod syndrome, (2) the need for detailed evaluation in seemingly “isolated” gene deletions and (3) the clinical utility of high-density copy number analysis for rapidly characterizing chromosomal lesions.

1H MRS allows brain phenotype differentiation in sisters with late onset ornithine transcarbamylase deficiency (OTCD) and discordant clinical presentations

We used 1H MRS to evaluate brain metabolic differences in sisters with partial ornithine transcarbamylase deficiency (OTCD) who had discordant clinical symptoms and urea synthetic capabilities to assess whether a brain biomarker of partial OTCD correlated with urea synthetic ability and clinical severity. We performed single voxel 3.0T 1H MRS in two adult sisters with partial OTCD, one symptomatic and one asymptomatic, in a stable medical state and compared it to one age matched adult control, as well as data collected on an additional 13 subjects with partial OTCD and 12 controls. Data from voxels placed in frontal and parietal white matter (FWM, PWM), posterior cingulate gray matter (PCGM), and thalamus (tha), were corrected for partial volume and analyzed using “LCModel”. All three subjects as well as the symptomatic mother of the two sisters, had neurocognitive testing, plasma ammonia levels, plasma amino acid, and urine organic acid analysis. Previous urea synthetic capabilities had been measured by stable isotope analysis. We found IQ scores to be inversely related to symptoms. Decreased myoinositol (mI) identified OTCD subjects, even the sister who is asymptomatic, in the posterior parietal white matter and frontal white matter. Brain metabolism is impaired in partial OTCD. Abnormal metabolism in apparently asymptomatic OTCD females may provide an explanation for neurocognitive impairments previously reported. The concentration of mI seen on 1H MRS in PWM and FWM in this family could be used to deduce clinical symptomatology and may serve as a non-invasive marker of brain liability in OTCD.

Poster Abstract #10: Preliminary Experience With Functional MRI (fMRI) Detects Altered Neural Networks Subserving Executive Function and Attention in Subjects With Partial Ornithine Transcarbamylase Deficiency (OTC)

Poster Abstract #10: Preliminary Experience With Functional MRI (fMRI) Detects Altered Neural Networks Subserving Executive Function and Attention in Subjects With Partial Ornithine Transcarbamylase Deficiency (OTC)

Poster Abstract #15: Preliminary Experience With MRS at 3T in Urea Cycle Disorders Detects Altered Metabolism in Partial Ornithine Transcarbamylase Deficiency

Poster Abstract #15: Preliminary Experience With MRS at 3T in Urea Cycle Disorders Detects Altered Metabolism in Partial Ornithine Transcarbamylase Deficiency

Evolution of adenoviruses as gene therapy vectors.

Evolution of adenoviruses as gene therapy vectors.

In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle

Urea cycle disorders are a group of inborn errors of hepatic metabolism that result in often life-threatening hyperammonemia and hyperglutaminemia. Clinical and laboratory diagnosis of partial deficiencies during asymptomatic periods is difficult, and correlation of phenotypic severity with either genotype and/or in vitro enzyme activity is often imprecise. We hypothesized that stable isotopically determined in vivo rates of total body urea synthesis and urea cycle-specific nitrogen flux would correlate with both phenotypic severity and carrier status in patients with a variety of different enzymatic deficiencies of the urea cycle. We studied control subjects, patients, and their relatives with different enzymatic deficiencies affecting the urea cycle while consuming a low protein diet. On a separate occasion the subjects either received a higher protein intake or were treated with an alternative route medication sodium phenylacetate/benzoate (Ucephan), or oral arginine supplementation. Total urea synthesis from all nitrogen sources was determined from [(18)O]urea labeling, and the utilization of peripheral nitrogen was estimated from the relative isotopic enrichments of [(15)N]urea and [(15)N]glutamine during i.v. co-infusions of [5-(amide)(15)N]glutamine and [(18)O]urea. The ratio of the isotopic enrichments of (15)N-urea/(15)N-glutamine distinguished normal control subjects (ratio = 0.42 +/- 0.06) from urea cycle patients with late (0.17 +/- 0.03) and neonatal (0.003 +/- 0.007) presentations irrespective of enzymatic deficiency. This index of urea cycle activity also distinguished asymptomatic heterozygous carriers of argininosuccinate synthetase deficiency (0. 22 +/- 0.03), argininosuccinate lyase deficiency (0.35 +/- 0.11), and partial ornithine transcarbamylase deficiency (0.26 +/- 0.06) from normal controls. Administration of Ucephan lowered, and arginine increased, urea synthesis to the degree predicted from their respective rates of metabolism. The (15)N-urea/(15)N-glutamine ratio is a sensitive index of in vivo urea cycle activity and correlates with clinical severity. Urea synthesis is altered by alternative route medications and arginine supplementation to the degree that is to be expected from theory. This stable isotope protocol provides a sensitive tool for evaluating the efficacy of therapeutic modalities and acts as an aid to the diagnosis and management of urea cycle patients.

Recombinant adenovirus gene transfer in adults with partial ornithine transcarbamylase deficiency (OTCD).

Human Gene TherapyVol. 10, No. 14 Recombinant Adenovirus Gene Transfer in Adults with Partial Ornithine Transcarbamylase Deficiency (OTCD)Mark L. Batshaw, James M. Wilson, Steven Raper, Marc Yudkoff, and Michael B. RobinsonMark L. BatshawSearch for more papers by this author, James M. WilsonSearch for more papers by this author, Steven RaperSearch for more papers by this author, Marc YudkoffSearch for more papers by this author, and Michael B. RobinsonSearch for more papers by this authorPublished Online:6 Jul 2004https://doi.org/10.1089/10430349950017068AboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byAbnormalities of Hepatic Protein MetabolismAdenoviral Vector-Based Vaccines and Gene Therapies: Current Status and Future Prospects13 March 2019Spliced: Boundary-work and the establishment of human gene therapy28 June 2017 | BioSocieties, Vol. 12, No. 2Adenoviruses7 March 2016The Ethics of Randomized Trials in Oncology25 November 2014Turning the Corner with Viral-based Gene Therapy—Development of the Rogue BiopharmaceuticalGene TherapyVirus-mediated gene delivery for human gene therapyJournal of Controlled Release, Vol. 161, No. 2Radioprotective gene therapy2 May 2011 | Expert Opinion on Biological Therapy, Vol. 11, No. 9The Death of Jesse Gelsinger: New Evidence of the Influence of Money and Prestige in Human Research1 June 2010 | American Journal of Law & Medicine, Vol. 36, No. 2-3Complement Component C1q and Anti-hexon Antibody Mediate Adenovirus Infection of a CAR-Negative Cell Line Van Tsai, Robin Varghese, Sundari Ravindran, Robert Ralston, and Gary Vellekamp30 December 2008 | Viral Immunology, Vol. 21, No. 4The gene delivery system for rheumatoid synoviumJapanese Journal of Clinical Immunology, Vol. 31, No. 1Gene therapy. An ethical profile of a new medical territory1 January 2006 | The Journal of Gene Medicine, Vol. 8, No. 11Replication Properties of Human Adenovirus In Vivo and in Cultures of Primary Cells from Different Animal SpeciesJournal of Virology, Vol. 80, No. 7CANCER GENE THERAPY CLINICAL TRIALSGene therapy for hemophilia?9 June 2005 | Journal of Thrombosis and Haemostasis, Vol. 3, No. 6Regulatory Aspects in the Development of Gene TherapiesGene therapy for genetic diseases: On the horizonClinical and Applied Immunology Reviews, Vol. 4, No. 6Endocrine Aspects of Cancer Gene Therapy31 October 2016 | Endocrine Reviews, Vol. 25, No. 1Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency1 January 2003 | Annals of Neurology, Vol. 55, No. 1Not so rare: errors of metabolism during the neonatal periodNewborn and Infant Nursing Reviews, Vol. 3, No. 4Gene Therapy Applications for Spine FusionSpine, Vol. 28, No. supplementTiter determination of Ad5 in blood: a cautionary note30 May 2003 | Gene Therapy, Vol. 10, No. 12The impact of adenovirus infection on the immunocompromised host1 January 2003 | Reviews in Medical Virology, Vol. 13, No. 3Ornithine transcarbamylase deficiency: a urea cycle defectEuropean Journal of Paediatric Neurology, Vol. 7, No. 3Gene therapy ethics and haemophilia: an inevitable therapeutic future?4 March 2003 | Haemophilia, Vol. 9, No. 2Adenoviral vectors: Systemic delivery and tumor targeting22 November 2002 | Cancer Gene Therapy, Vol. 9, No. 12Novel, Chimpanzee Serotype 68-Based Adenoviral Vaccine Carrier for Induction of Antibodies to a Transgene ProductJournal of Virology, Vol. 76, No. 6Subcutaneous Administration of a Replication-Competent Adenovirus Expressing HSV-tk to Cotton Rats: Dissemination, Persistence, Shedding, and Pathogenicity Oliver Wildner and John C. Morris6 July 2004 | Human Gene Therapy, Vol. 13, No. 1Lethal Toxicity, Severe Endothelial Injury, and a Threshold Effect with High Doses of an Adenoviral Vector in Baboons Núria Morral, Wanda K. O'Neal, Karen Rice, M. Michelle Leland, Pedro A. Piedra, Estuardo Aguilar-Córdova, K. Dee Carey, Arthur L. Beaudet, and Claire Langston6 July 2004 | Human Gene Therapy, Vol. 13, No. 1Quantitative Analysis of Adenovirus-Specific CD4+ T-Cell Responses from Healthy Adults Melanie Olive, Laurence C. Eisenlohr, and Phyllis Flomenberg9 July 2004 | Viral Immunology, Vol. 14, No. 4Complement activation by recombinant adenoviruses24 January 2002 | Gene Therapy, Vol. 8, No. 23Adenovirus Type 7 Induces Interleukin-8 Production via Activation of Extracellular Regulated Kinase 1/2Journal of Virology, Vol. 75, No. 14Update on adenovirus and its vectorsJournal of General Virology, Vol. 81, No. 11Adenovirus-mediated gene therapy to liver grafts: Successful gene transfer by donor pretreatmentSurgery, Vol. 128, No. 2Viral Vectors for Gene TransferDrugs, Vol. 60, No. 2Altering the pathway to human gene therapy24 December 2001 | Clinical Genetics, Vol. 58, No. 1Latest Developments in Gene Transfer Technology: Achievements, Perspectives, and Controversies over Therapeutic Applications1 January 2009 | STEM CELLS, Vol. 18, No. 1 Volume 10Issue 14Sep 1999 To cite this article:Mark L. Batshaw, James M. Wilson, Steven Raper, Marc Yudkoff, and Michael B. Robinson.Recombinant Adenovirus Gene Transfer in Adults with Partial Ornithine Transcarbamylase Deficiency (OTCD).Human Gene Therapy.Sep 1999.2419-2437.http://doi.org/10.1089/10430349950017068Published in Volume: 10 Issue 14: July 6, 2004PDF download

Developing adenoviral-mediated in vivo gene therapy for ornithine transcarbamylase deficiency.

There are a number of reasons for choosing ornithine transcarbamylase (OTC) deficiency as a candidate for gene therapy: the gene has been cloned; the disorder is relatively common; the current clinical outcome is poor; and there are authentic animal models. In considering the development of gene therapy for OTC deficiency, we focused on the use of in vivo gene therapy with an adenoviral vector. Using the partially OTC-deficient sparse fur mouse we found transduction and expression could be achieved using an intravenous infusion of a recombinant adenovirus containing the OTC cDNA. The results were transient as a result of immune activation in response to the vector and vector-transduced cells. By modifying the adenoviral construct, creating an E1 deletion-E2 temperature-sensitive mutation, we blunted the cytotoxic T lymphocyte immune response and achieved correction of biochemical abnormalities for 2-3 months. We also found that transduction and expression following gene transfer occurred sufficiently rapidly to protect against acute hyperammonaemia within 24 h. Subsequent preclinical studies in mice and non-human primates demonstrated that E1-E4-deleted vectors had a substantially improved safety profile and similar efficacy. With this evidence of efficacy and safety of adenoviral vectors, we are embarking on a phase I trial of intravascular gene transfer using an E1-E4-deleted vector in adults with partial OTC deficiency.

Hyperammonemic coma due to parenteral nutrition in a woman with heterozygous ornithine transcarbamylase deficiency

Ornithine transcarbamylase deficiency is an X-linked disorder of the urea cycle that can cause hyperammonemic encephalopathy in hemizygous males and heterozygous females. Affected females typically limit protein intake in their diet. This case report describes a 36-year-old woman with ulcerative colitis who went into hyperammonemic coma after administration of total parenteral nutrition. A similar episode of coma had occurred 7 years earlier after she delivered a normal boy. Heterozygous ornithine transcarbamylase deficiency was diagnosed based on a positive allopurinol tolerance test result after elevated levels of plasma glutamine and low plasma citrulline were detected. The protein load associated with parenteral alimentation resulted in symptomatic expression of this partial enzyme deficiency in this unique case. Partial ornithine transcarbamylase deficiency must always be considered in adult women and men with hyperammonemia who have normal liver function test results.

Reversal of Anorexia in a Child with Partial Ornithine Transcarbamylase Deficiency by Cyproheptadine Therapy

Reversal of Anorexia in a Child with Partial Ornithine Transcarbamylase Deficiency by Cyproheptadine Therapy