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Ornithine transcarbamylase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Ornithine transcarbamylase deficiency (OTCD) is the most common inherited disorder of the urea cycle. The most classic of the infantile urea cycle presentations is that of OTCD in the male. Onset is in the neonatal period with coma and/or convulsions, and in the absence of effective intervention, it is rapidly fatal. A sizable number of males have variant enzymes and a milder and later presentation, but hyperammonemia can still be fatal, even in adulthood. Females who have two X chromosomes have varying phenotypes mainly depending on the proportion of active and inactive X chromosomes.
Introduction
Published in Tina Stevens, Stuart Newman, Biotech Juggernaut, 2019
Eighteen-year old Jesse had suffered from a rare metabolic genetic disease, ornithine transcarbamylase deficiency (OTCD). OTCD prevents the breakdown of ammonia in the body and for children with severe cases it can lead to early death. But Jesse was not sick. His mild version of the disease was controlled by diet and medication. Researchers affiliated with the University of Pennsylvania, keen to test the vaunted promise of manipulating genes to treat disease, told Jesse and his parents that a trial to test a new method for delivering the normal genes to patients’ livers was relatively safe. They were told, too, that the results could help babies with more severe OTCD. Jesse also harbored a hope: perhaps someday he would be free of his exacting 32 pills-per-day medication regimen. Primed by promises, Jesse entered the trial generous-hearted and hopeful, and on September 13, 1999 he received an injected delivery of new genes. But a few days later he suffered a massive inflammatory response triggering multiple organ failure and brain death. Ultimately, his devastated parents removed him from life support.
Inborn errors of metabolism
Published in Martin Andrew Crook, Clinical Biochemistry & Metabolic Medicine, 2013
Urea cycle defects are an important cause of hyperammonaemia and there may also be raised urinary orotic acid concentration, an intermediate metabolite of pyrimidine synthesis derived from carbamyl phosphate. The urea cycle defects can present not only with severe hyperammonaemia, but also with a respiratory alkalosis and low plasma urea concentration (Fig. 27.2). Carbamyl phosphate synthetase (CPS) deficiency is a urea cycle disorder in which, unlike other defects in this pathway, urinary orotic acid is not raised. Ornithine transcarbamylase deficiency is probably the most common urea cycle defect and is sex linked.
Onasemnogene abeparvovec for the treatment of spinal muscular atrophy
Published in Expert Opinion on Biological Therapy, 2022
Hugh J. McMillan, Crystal M. Proud, Michelle A. Farrar, Ian E. Alexander, Francesco Muntoni, Laurent Servais
The preferred vector for a gene therapy targeting the central nervous system (CNS) is derived from adeno-associated virus (AAV), a dependent parvovirus. Recombinant AAV vectors are suitable for gene therapy because of their capacity to transduce both dividing and non-dividing cells and confer long-term transgene expression in non-dividing cells, primarily as a non-integrating episome [31–34]. In addition, AAV-based therapies have relatively low immunogenicity compared with other viral vectors, such as adenovirus. The importance of a patient’s immune response to a viral vector was first demonstrated by a patient with ornithine transcarbamylase deficiency who died in 1999 after suffering complications from an adenovirus-mediated gene transfer [35]. This case highlighted the need to consider other less immunogenic viral vectors for gene therapy applications targeting genetic disease.
Hyperammonemia in the setting of Roux-en-Y gastric bypass presenting with osmotic demyelination syndrome
Published in Journal of Community Hospital Internal Medicine Perspectives, 2021
Carly Rosenberg, Michael Rhodes
With the increasing rate of obesity in the USA, bariatric surgery continues to be offered as a weight loss treatment. However, over time, there have been multiple case reports on the correlation between RYGB and hyperammonemia in the absence of cirrhosis or liver disease [1–4]. The onset of hyperammonemic encephalopathy after RYGB has been shown to present at various intervals, ranging from months to years [1]. In this case, the patient had a RYGB approximately 20 years prior to presentation. RYGB hyperammonemia has been observed more so in women, and in some cases, women with X-linked heterozygous ornithine transcarbamylase deficiency who had previously been asymptomatic [1]. Multiple nutritional deficiencies have been associated with this syndrome as well including hypoalbuminemia, multiple amino acid deficiencies, hypoglycemia and low zinc levels, many of which were seen in this patient [2]. Nutritional deficiencies are thought to play a role in the urea cycle, interfering with the elimination of ammonia. In addition, RYGB alters the anatomy of the gastrointestinal system, which can cause intestinal overgrowth, leading to the production of ammonia from urease-producing bacteria (Figure 2) [1,2].
Merits of the ‘good’ viruses: the potential of virus-based therapeutics
Published in Expert Opinion on Biological Therapy, 2021
Qianyu Zhang, Wen Wu, Jinqiang Zhang, Xuefeng Xia
The hope of gene delivery has been buoyed by the introduction of viral vectors. In this regard, viruses are nano-sized particles composed of nucleic acid coding for the genetic information and capsids which are composed of proteins as the outer layer. The viral genome can thus be manipulated and substituted with the therapeutic nucleic acid of interest. Recombinant viral vectors were then used as the first generation of gene delivery tools in clinical trials, which was to use retroviral vectors to deliver therapeutic genes to blood cells for the treatment of adenosine delaminate deficiency, which is the cause of severe combined immunodeficiency (ADA-SCID) [50–52]. In 1999, gene therapy met with a great setback with the death of a young patient, Jesse Gelsinger, who was treated with adenoviral vector for ornithine transcarbamylase deficiency [53]. He died of the severe immune response after a very high dose of adenovirus which ultimately led to multi-organ failure. He was the first patient that died on a gene therapy trial due to vector-associated toxicity. Later, when treating children with X-linked SCID (X-SCID), 18 of 20 participants experienced restored immunity. However, five patients subsequently developed leukemia due to the integration of the retroviral vector near a proto-oncogene locus, which triggered T cell proliferation, resulting in the death of one patient [54,55]. These results presented promise in gene delivery using viral vectors as well as the need for safe gene delivery tactics that are more meticulously designed.