The Cerebellar Ataxias and Hereditary Spastic Paraplegias
John W. Scadding, Nicholas A. Losseff in Clinical Neurology, 2011
The intermittent metabolic ataxias of childhood are rare. Affected children have a fluctuating cerebellar ataxia which tends to appear for a few weeks and then remit. Seizures, episodes of coma and cognitive impairment are often associated. Attacks may arise spontaneously or in association with infections or dietary changes. Patients with X-linked ornithine transcarbamylase deficiency may be only mildly affected in between attacks of severe encephalopathy and cerebral oedema. A photosensitive rash is characteristic of Hartnup disease. The most likely metabolic derangements are: Hyperammonaemias (several autosomal recessive forms and X-linked ornithine transcarbamylase deficiency)Aminoacidurias (Hartnup disease, maple syrup urine disease and isovaleric acidaemia)Derangements of pyruvate or lactate metabolism (various autosomal recessive or X-linked inborn errors including pyruvate dehydrogenase deficiency and pyruvate carboxylase deficiency).
Inborn errors of metabolism
Martin Andrew Crook in 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.
Ornithine transcarbamylase deficiency
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
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.
A practical guide to the handling and administration of personalized transcriptionally attenuated oncolytic adenoviruses (PTAVs)
Published in OncoImmunology, 2018
Christopher Larson, Bryan Oronsky, Gina Varner, Scott Caroen, Erica Burbano, Elisa Insel, Farah Hedjran, Corey A. Carter, Tony R. Reid
Adenoviruses (Ad),1 discovered in 1953, and associated in humans with mild cold-like symptoms, possess distinct advantages for oncolytic virotherapy.2 These advantages include the following: a lytic replication cycle, high stability, ease of manufacture at high titers, the availability of animal models such as Syrian hamsters and cotton rats supporting Ad replication, efficient genome transfer, low pathogenicity, the lack of any neoplastic or chronic disease associated with adenoviruses in immunocompetent patients, and long term accumulated clinical experience (over a decade) from multiple phase I and phase II trials demonstrating favorable safety and tolerability.3,4 Only in one isolated and well-known case of a clinical trial participant with severe ornithine transcarbamylase deficiency was an adenoviral vector directly responsible for the death of a patient.5 In contrast, the main adverse events experienced with ONYX-015, as the most extensively tested ‘un-armed’ oncolytic virus (OV), along with its successor, H101, approved and marketed in China under the name Oncorine6 for the treatment of head and neck cancers, were mild short-lived flu-like symptoms in >90% of the patients and transient grade I/II hepatic toxicities in about 20% of the patients.7
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.
Related Knowledge Centers
- Ataxia
- Carbamoyl Phosphate
- Citrulline
- Enzyme
- Hyperammonemia
- Lethargy
- Ornithine
- Urea Cycle
- Ornithine Transcarbamylase
- X-Linked Recessive Inheritance