Ornithine transcarbamylase deficiency

Ornithine transcarbamylase deficiency. This is the most common of the urea cycle defects. Presentation is variable, ranging from a fulminant, fatal disorder of neonates to a schizophrenic-like illness in an otherwise healthy adult. Males characteristically fare more poorly than do females with this X-linked disorder because of random inactivation (lyonization) of the X chromosome. If inactivation affects primarily the X chromosome bearing the mutant OTC gene, then a more favorable outcome can be anticipated. Conversely, the unfavorably lyonized female has a more active disease. 

Yudkoff, M., Daikhin,Y., Nissim, I., Jawad,A.,Wilson, J. and Batshaw, M. B. In vivo nitrogen metabolism in ornithine transcarbamylase deficiency. /. Clin. Invest. 98 2167-2173, 1996. 

Ye, X., Robinson, M. B., Batshaw, M. L., Furth, E. E., Smith, I. and Wilson, J. M. Prolonged metabolic correction in adult ornithine transcarbamylase-deficient mice with adenoviral vectors. / Biol. Chem. 271 3639-3646,1996. 

Urea cycle disorders (UCDs) Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with UCDs, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders (see Precautions). 

Raper, S. E., Chirmule, N., Lee, F. S., Wivel, N. A., Bagg, A., Gao, G. P., Wilson, J. M. and Batshaw, M. L. (2003). Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol. Genet. Metab. 80, 148-158. 

A number of inherited disorders of urea cycle metabolism are known. Hy per-ammonemia I and II are associated with CPS I and ornithine transcarbamylase deficiencies, respectively. Citrullinemia, arginosuccinic aciduria, and argininemia are associated with low levels of arginosuccinic acid synthetase, arginosuccinase, and arginase, respectively. All such disorders are associated with mental retardation, convulsions, and failure to thrive if not treated. Treatment involves the feeding of low-protein diets or, experimentally, the administration of a-keto analogs of essential amino acids instead of protein. 

Maestri, N.E., Brusilow, S.w., Clissold, D.B., Bassett, S.S. Long-term treatment of girls with ornithine transcarbamylase deficiency. New Engl. X Med. 1996 335 855-859... 

Tuchman, M., Matsuda, I., Munnich, A., Malcolm, S., Strautnieks, S., Briede, T. Proportions of spontaneous mutations in males and females with ornithine transcarbamylase deficiency. Amer. X Med. Genet. 1995 55 67-70... 

Deaths have occurred after the use of valproate in patients with ornithine transcarbamylase deficiency (SED-12, 133) (36) (SED-13, 149) (37). Additional evidence points to a need for caution in patients with any enzyme disorder. 

Rapp B, Haberle J, Linnebank M, Wermuth B, Marquardt T, Harms E, et al. Genetic analysis of carbamoylphosphate synthetase I and ornithine transcarbamylase deficiency using fibroblasts. Eur J Pediatr 2001 160 283-7. 

The first death attributable to gene therapy occurred in September 1999, when an 18-year-old patient with ornithine transcarbamylase deficiency died, apparently as a direct result of the experimental gene therapy studies. 

Xp21.1 68.97 OTC Ornithine carbamoyltransferase 300461 Ornithine transcarbamylase deficiency, Duchenne muscular dystrophy... 

Association of Carbamyl Phosphate Synthetase with Ornithine Transcarbamylase Deficiency... 

It may be concluded that in many cases of an ornithine transcarbamylase deficiency, there is an associated carbamyl phosphate deficiency, usually of moderate degree. It is because of this that it has even been suggested (E2) that hyperammonemia might not be due solely to ornithine transcarbamylase deficiency. This view cannot be correct in at least two cases where the carbamyl phosphate synthetase was within the normal, albeit low normal, range. 

Of a total of 11 known cases, 10 are females and 1 is a male, who had a differing type of ornithine transcarbamylase deficiency (L6). Such a preponderance of females suggests that the condition is sex-limited, finding expression only in the female. Of the ten female cases, two sibs have been affected in one family as well as, in all probability, the mother. In another family, both mother and her female infant were certainly affected. The latter in particular suggests that the defect is inherited as... 

Levin et al. has shown that whereas the ornithine transcarbamylase deficiency is severe and critical in most cases of hyperammonemia, in one child, a boy, the enzyme activity was reduced to a lesser extent (L6). Further investigations showed that other differences between the enzyme in this child and in others affected, existed. Thus the affinities of the enzyme for both carbamyl phosphate and ornithine were markedly different in this child from the others. On the basis of these findings they suggested that this constituted a distinct genetic variant, which could explain its occurrence in a male infant whereas all other reported cases of hyperammonemia were in females. 

Carbamylphosphate synthetase deficiency, ornithine transcarbamylase deficiency, and argininosuccinic acid synthetase deficiency Cystinosis Friedreich s ataxias Xerostomia and keratoconjunctivitis Myoclonus... 

Gordon, N., 2003. Ornithine transcarbamylase deficiency A urea cycle defect. Eur J Paediatr Neurol, 7(3) pp. 115-121... 

Thakur, V, et al.2006. Fatal cerebral edema from late-onset ornithine transcarbamylase deficiency in a juvenile male patient receiving valproic acid. Pediatr Crit Care Med, 7(3) pp. 273-276... 

As a primary player in metabolism, many inborn errors affect liver function and health. Many harm the liver acutely, and some predispose to chronic liver disease. Unfortunately many of these disorders are not susceptible to dietary or medical therapies, making liver (or sometimes bone marrow) transplant the only means of treatment. Transplant can alternatively serve as a means of effective treatment. In disorders including ornithine transcarbamylase deficiency and GSD type la, liver transplant is thought to be curative. Bone marrow transplant helps with visceral symptoms in many storage disorders as well, providing an adjunct to enzyme or substrate replacement therapies. 

GaUagher RC, et al. Significant hepatic involvement in patients with ornithine transcarbamylase deficiency. J Pediatr. 2014 164(4) 720-725.e6. 

Peterson DE. Acute postpartum mental status change and coma caused by previously imdiagnosed ornithine transcarbamylase deficiency. Obstet Gynecol. 2003 102(5 Pt 2) 1212-5. 

Mendez-Figueroa H, et al. Management of ornithine transcarbamylase deficiency in pregnancy. Am J PerinatoL 2010 27(10) 775-84. 

Urea cycle Ornithine transcarbamylase deficiency Orotic add TT... 

Batshaw, M.L. et al.. Recombinant adenovirus gene transfer in adults with partial ornithine transcarbamylase deficiency (OTCD), Hum. Gene Ther., 10,2419,1999. 

Finkelstein, J.E., et at. Use of Denaturing Gradient Gel-Electrophoresis for Detection of Mutation and Prospective Diagnosis in Late Onset Ornithine Transcarbamylase Deficiency. Genomics, 1990. 7(2) p. 167-172. 

Several other trials are in progress and await completion and reporting of the data. Diseasesunder study include alphaj-antitrypsin deficiency, Fanconi s anemia, Gaucher s disease. Hunter s syndrome, Canavan s disease, limb girdle muscular dystrophy, amyotrophic lateral sclerosis, ornithine transcarbamylase deficiency, and junctional epidermolysis bullosa. 

With the death of a 19-year-old research subject in a clinical trial designed for the study of ornithine transcarbamylase deficiency, the field of gene therapy research entered a new era in that this was the first death attributable to gene therapy itself Not only was there widespread puhlicify in the print media and... 

Raper SE, ChirmuleN, LeeFS, et al. Lethal systemic inflammatoiy response syndrome in a patient with partial ornithine transcarbamylase deficiency following intravascular administration of recombinant adenoviral vector. Submitted. 

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