X-Linked Transmission of Ornithine-Transcarbamylase Deficiency

Scott, C. Ronald; Teng, CeciliaChiang; Goodman, S. I.; Greensher, Arnold; Mace, John

doi:10.1016/s0140-6736(72)92756-0

Cited by 17 publications

(3 citation statements)

References 10 publications

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“…T h e clinical course and pedigree of this patient are similar to that of other male patients with this genetic lesion [5,12,18,24,261, and substantiate the X-linked dominant transmission of the defect with varying degrees of illness in females. T h e pathogenesis of the disorder has been discussed extensively in previous reviews [5,6,15,25,291.…”

Section: Discussionsupporting

confidence: 75%

Metabolic and Genetic Studies of a Family with Ornithine Transcarbamylase Deficiency

et al. 1974

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ExtractW e have described a patient with ornithine transcarbamylase (OTC) deficiency.T h e clinical course and pedigree substantiate the X-linked transmission of the defect with varying degrees of illness in females. Because orotic aciduria accompanied hyperammonemia in the patient, orotic acid was measured as an indication of a partial OTC deficiency after ammonia and protein loading in members of the patient's family. Both the mother, a n obligate carrier, and an aunt, the only symptomatic female in this pedigree, had hyperammonemia after the ingestion of ammonium chloride. They also had significant orotic aciduria after a protein load as did the two female cousins whose ammonium tolerance was normal. T h e maternal grandmother excreted a large amount of orotic acid in her urine relatively consistently. 'These data suggest that the two female cousins and the maternal grandmother are asymptomatic female heterozygotes despite their normal ammonium loading tests. SpeculationProtein loading in the form of a relatively palatable and innocuous meal, followed by determination of orotic acid content in urine, may prove to be a sensitive, noninvasive, and easy means to identify female carriers of ornithine transcarbamylase deficiency.

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Section: Discussionsupporting

confidence: 75%

Metabolic and Genetic Studies of a Family with Ornithine Transcarbamylase Deficiency

et al. 1974

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“…A considerable body of evidence supports this proposal for marsupials and eutherians (Ohno, 1969;Lyon, 1974;Cooper et al 1977). We have chosen four enzymes known to be Xlinked in man, namely glucose-6-phosphate dehydrogenase (G6PD) (Beutler & Yoshida, 1973), phosphoglycerate kinase (PGK) (Chen et al 1971), a-galactosidase (Kint, 1970), and ornithine transcarbamylase (OTC) (Campbell et al 1971;Scott et al 1972), and examined them for electrophoretically detectable polymorphism in kangaroos, in which no previous information on their inheritance was available. We have found that G6PD (Johnston & Sharman, 1975), PGK (Cooper et al 1977) and a-galactosidase (Cooper et al unpublished data) exhibit electrophorectic variation in kangaroos which shows their loci to be X-linked.…”

Section: Selection Of An Unbiased Sample Of X-linked Loci (A) Kangaroosmentioning

confidence: 99%

A comparison of genetic variability atX-linked and autosomal loci in kangaroos, man andDrosophila

et al. 1979

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This paper tests the hypothesis that haplodiploidy or X linkage leads to less genetic variability. Although haplodiploid organisms exhibit a low level of genetic variability the wide variation existing between different diploid organisms implies that factors other than the genetical system could also be responsible. In order to test the hypothesis critically it is necessary to compare the level of genetic variability between .X-linked and autosomai genes within a closely related group of organisms. For kangaroos, the ascertainment bias for .XMinked loci has been removed by assuming the correctness of Ohno's law of conservation of the mammalian X, i.e. that genes found to be .X-linked in man can be assumed to be X-linked in kangaroos. For Man and Drosophila, it has been assumed that the percentage of the karyotype which is X chromosome can be used as the expectation for the percentage of .XMinked polymorphisms. No difference between the two classes of loci is evident in kangaroos and man for percentage polymorphism. The data however have confidence limits which would allow autosomai loci to have three times greater percentage polymorphism. In Drosophila the published data of Prakash show that autosomai loci are polymorphic about twice as frequently as are their X-linked counterparts. Thus there may be a modest reduction in percentage polymorphism as a result of X-linkage (i.e. haplodiploidy). No reduction in the number of alleles per locus or average heterozygosity at those loci which are polymorphic is evident in kangaroos, man, or Drosophila. More data on more X-linked enzymes are necessary to establish firmly that there is a real reduction in percentage polymorphism and to estimate its extent. The kangaroo data are incompatible with the hypothesis that a large fraction of the variability is maintained by simple overdominance since overdominance is very unlikely in the quasi-haploid genetical system which results from the paternal X inactivation mode of dosage compensation used by kangaroos. This is the first report on level of enzymic variability in marsupials. 17% of autosomai loci and 18% of X-linked loci are polymorphic, average heterozygosity is 4 % for % Present address: autosomal and 4 % for X-linked loci and number of alleles per locus is 1-25 for autosomal and 1-21 for X-linked loci. These figures are somewhat lower than for eutherian mammals.

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“…2 Most inborn errors of metabolism are inherited as recessive traits with the exception of X-linked ornithine transcarbamylase deficiency. 3 The pathology of UCDs is characterized primarily by hyperammonemia and encephalopathy, with symptoms ranging from lifethreatening episodes in newborns to recurrent headaches in adults. 4,5 The reported incidence of all UCDs is approximately 1 in 25,000 live births in the United States, a severe condition with high mortality rates that affects thousands of families in the United States, with an estimated incidence of 1 in 57,000 live births.…”

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Two Hypomorphic Alleles of Mouse Ass1 as a New Animal Model of Citrullinemia Type I and Other Hyperammonemic Syndromes

Pérez

Jaubert

Guénet

et al. 2010

The American Journal of Pathology

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Citrullinemia type I (CTLN1 , OMIM# 215700) is an inherited urea cycle disorder that is caused by an argininosuccinate synthetase (ASS) enzyme deficiency. In this report , we describe two spontaneous hypomorphic alleles of the mouse Ass1 gene that serve as an animal model of CTLN1. These two independent mouse mutant alleles , also described in patients affected with CTLN1 , interact to produce a range of phenotypes. While some mutant mice died within the first week after birth , others survived but showed severe retardation during postnatal development as well as alopecia , lethargy , and ataxia. Notable pathological findings were similar to findings in human CTLN1 patients and included citrullinemia and hyperammonemia along with delayed cerebellar development , epidermal hyperkeratosis , and follicular dystrophy. Standard treatments for CTLN1 were effective in rescuing the phenotype of these mutant mice. Based on our studies , we propose that defective cerebellar granule cell migration secondary to disorganization of Bergmann glial cell fibers cause cerebellar developmental delay in the hyperammonemic and citrullinemic brain , pointing to a possible role for nitric oxide in these processes. These mouse mutations constitute a suitable model for both mechanistic and preclinical studies of CTLN1 and other hyperammonemic encephalopathies and, at the same time, underscore the importance of complementing knockout mutations with hypomorphic mutations for the generation of animal models of human genetic diseases.

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X-Linked Transmission of Ornithine-Transcarbamylase Deficiency

Cited by 17 publications

References 10 publications

Metabolic and Genetic Studies of a Family with Ornithine Transcarbamylase Deficiency

Metabolic and Genetic Studies of a Family with Ornithine Transcarbamylase Deficiency

A comparison of genetic variability atX-linked and autosomal loci in kangaroos, man andDrosophila

Two Hypomorphic Alleles of Mouse Ass1 as a New Animal Model of Citrullinemia Type I and Other Hyperammonemic Syndromes

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