Sustaining hypercitrullinemia, hypercholesterolemia and augmented oxidative stress in Japanese children with aspartate/glutamate carrier isoform 2-citrin-deficiency even during the silent period

Nagasaka, Hironori; Okano, Yoshiyuki; Tsukahara, Hirokazu; Shigematsu, Yosuke; Momoi, Toru; Yorifuji, Junko; Miida, Takashi; Ohura, Toshihiro; Kobayashi, Keiko; Saheki, Takeyori; Hirano, Ken‐ichi; Takayanagi, Masaki; Yorifuji, Tohru

doi:10.1016/j.ymgme.2009.01.009

Cited by 38 publications

(30 citation statements)

References 30 publications

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“…43 However, a clear role for oxidative and nitrative stress in CTLN1 has not yet been elucidated. 44 Few reports found increased biomarkers for oxidative stress associated with sustained hypercitrullinemia, 45 or decreased total antioxidant capacity in brain with no changes in antioxidant enzyme activities or MDA formation. 42 In our mouse model, the higher content of MDA-reactive material found in mutant cerebella compared to controls can be linked to either increased oxidative stress, a decreased capacity for glutathione peroxidase/glutathione reductase to catabolyze lipid hydroperoxides, or a combination of both processes.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Mice with impaired MAS function due to decreased branched-chain amino acid catabolism exhibit increased skeletal muscle LPR [58], and administration of the MAS inhibitor aminooxyacetate is associated with increased LPR in isolated guinea pig cerebral cortical synaptosomes [59]. MAS disruption may be associated with an LPR increase even when ammonia levels are normal, as in patients with pre-symptomatic adult-onset type II citrullinemia [60].…”

Section: Hyperammonemiamentioning

confidence: 99%

Potential Non-Hypoxic/Ischemic Causes of Increased Cerebral Interstitial Fluid Lactate/Pyruvate Ratio: A Review of Available Literature

2011

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Microdialysis, an in vivo technique that permits collection and analysis of small molecular weight substances from the interstitial space, was developed more than 30 years ago and introduced into the clinical neurosciences in the 1990s. Today cerebral microdialysis is an established, commercially available clinical tool that is focused primarily on markers of cerebral energy metabolism (glucose, lactate, and pyruvate) and cell damage (glycerol), and neurotransmitters (glutamate). Although the brain comprises only 2% of body weight, it consumes 20% of total body energy. Consequently, the ability to monitor cerebral metabolism can provide significant insights during clinical care. Measurements of lactate, pyruvate, and glucose give information about the comparative contributions of aerobic and anaerobic metabolisms to brain energy. The lactate/pyruvate ratio reflects cytoplasmic redox state and thus provides information about tissue oxygenation. An elevated lactate pyruvate ratio (>40) frequently is interpreted as a sign of cerebral hypoxia or ischemia. However, several other factors may contribute to an elevated LPR. This article reviews potential non-hypoxic/ischemic causes of an increased LPR.

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“…Citrin deficiency currently remains a perplexing and poorly recognized disorder (11,12). In particular, a description of post-NIccd clinical presentations before cTLN2 onset is rather limited, although abnormal metabolic profiles at this stage have been reported by Nagasaka et al (13). We performed a comprehensive review in a citrin-deficient cohort obtained from a Chinese pediatric center, to explore…”

Section: Introductionmentioning

confidence: 99%

Genotypic and phenotypic features of citrin deficiency: Five-year experience in a Chinese pediatric center

Song

Deng²,

Chen³

et al. 2011

Int J Mol Med

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Abstract. citrin is a liver-type aspartate/glutamate carrier (AGc) encoded by the gene SLc25A13. Two phenotypes for human citrin deficiency have been described, namely the adult-onset citrullinemia type II (cTLN2) and the neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). However, citrin deficiency currently remains a perplexing and poorly recognized disorder. In particular, description of postNIccd clinical presentations before cTLN2 onset is rather limited. Analysis of SLC25A13 mutations, identification of dysmorphic erythrocytes, hepatobiliary scintigraphic imaging and investigation of post-NIccd clinical presentations were performed in a citrin-deficient cohort comprised of 51 cases of children diagnosed with citrin deficiency in a Chinese pediatric center. Twelve SLc25A13 mutations were detected in this cohort, including the novel V411M and G283X mutations. Among the 51 citrin-deficient subjects, 7 cases had echinocytosis, which was associated with more severe biochemical abnormalities. delayed hepatic discharge and bile duct/bowel visualization were common scintigraphic findings. Moreover, 9 of the 34 post-NIccd cases demonstrated concurrent failure to thrive and dyslipidemia, constituting a clinical phenotype different from NIccd and cTLN2. The novel mutations, echinocytosis, hepatobiliary scintigraphic features and the novel clinical phenotype in this study expanded the genotypic and phenotypic spectrum of citrin deficiency, and challenge the traditionally-assumed 'apparently healthy' period after the NIccd state for this disease entity.

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Sustaining hypercitrullinemia, hypercholesterolemia and augmented oxidative stress in Japanese children with aspartate/glutamate carrier isoform 2-citrin-deficiency even during the silent period

Cited by 38 publications

References 30 publications

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

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

Potential Non-Hypoxic/Ischemic Causes of Increased Cerebral Interstitial Fluid Lactate/Pyruvate Ratio: A Review of Available Literature

Genotypic and phenotypic features of citrin deficiency: Five-year experience in a Chinese pediatric center

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