Possible clinical and histologic manifestations of adult-onset type II citrullinemia in early infancy

doi:10.1067/mpd.2001.113361

The Journal of Pediatrics

Volume 138, Issue 5, May 2001, Pages 741-743

https://doi.org/10.1067/mpd.2001.113361 Get rights and content

Abstract

We describe 2 patients with adult-onset type II citrullinemia who developed transient hypoproteinemia and jaundice in early infancy. Liver histology showed a marked fatty change and fibrosis. After the patients had lived without symptoms to the ages of 5 and 16 years, respectively, the diagnosis was made by genetic analysis. (J Pediatr 2001;138:741-3)

Section snippets

Case 1

A 2-month-old boy was brought to a local hospital with a complaint of abdominal distension. He was found to have ascites caused by hypoproteinemia (total protein 3.7 g/dL and albumin 2.0 g/dL). Total (7.6 mg/dL) and direct (3.4 mg/dL) bilirubin concentrations were elevated. The alkaline phosphatase level was 991 IU/L, and the γ-glutamyl transpeptidase level was 130 IU/L. Prothrombin time was markedly prolonged (61 seconds). His serum ammonia concentration was slightly elevated (87 μg/dL) but

Case 2

A 2-month-old girl was evaluated for jaundice; the serum levels of total (11.1 mg/dL) and direct (3.6 mg/dL) bilirubin were elevated. Aspartate aminotransferase level was 86 IU/L; alanine aminotransferase level, 23 IU/L; γ- glutamyl transpeptidase level, 152 IU/L; alkaline phosphatase level, 1744 IU/L; and bile acid concentration, 320.1 μmol/L. Serum protein concentrations were decreased. The lowest values were as follows: total protein, 4.0 g/dL; albumin, 3.5 g/dL; fibrinogen, 68 mg/dL;

Discussion

In early infancy, both of these patients had a marked decrease in serum protein concentrations and a moderate elevation in total bilirubin concentration, neither of which is a common sign of CTLN2. They had characteristic liver histologic findings that might be compatible with CTLN2. Other metabolic diseases including Wilson’s disease, hemachromatosis, glycogen storage disease, and cytomegalovirus and Epstein-Barr virus infections were ruled out in both cases. Computed tomography scan or

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Cited by (89)

Analysis of daily energy, protein, fat, and carbohydrate intake in citrin-deficient patients: Towards prevention of adult-onset type II citrullinemia
2021, Molecular Genetics and Metabolism
Patients with citrin deficiency during the adaptation/compensation period exhibit diverse clinical features and have characteristic diet of high protein, high fat, and low carbohydrate. Japanese cuisine typically contains high carbohydrate but evaluation of diet of citrin-deficient patients in 2008 showed a low energy intake and a protein:fat:carbohydrate (PFC) ratio of 19:44:37, which indicates low carbohydrate consumption rate. These findings prompted the need for diet intervention to prevent the adult onset of type II citrullinemia (CTLN2). Since the publication of the report about 10 years ago, patients are generally advised to eat what they wish under active dietary consultation and intervention. In this study, citrin-deficient patients and control subjects living in the same household provided answers to a questionnaire, filled-up a maximum 6-day food diary, and supplied physical data and information on medications if any. To study the effects of the current diet, the survey collected data from 62 patients and 45 controls comparing daily intakes of energy, protein, fat, and carbohydrate. Food analysis showed that patient's energy intake was 115% compared to the Japanese standard. The confidence interval of the PFC ratio of patients was 20–22:47–51:28–32, indicating higher protein, higher fat and lower carbohydrate relative to previous reports. The mean PFC ratio of female patients (22:53:25) was significantly different from that of male patients (20:46:34), which may explain the lower frequency of CTLN2 in females. Comparison of the present data to those published 10 years ago, energy, protein, and fat intakes were significantly higher but the amount of carbohydrate consumption remained the same. Regardless of age, most patients (except for adolescents) consumed 100–200 g/day of carbohydrates, which met the estimated average requirement of 100 g/day for healthy individuals. Finally, patients were generally not overweight and some CTLN2 patients were underweight although their energy intake was higher compared with the control subjects. We speculate that high-energy of a low carbohydrate diet under dietary intervention may help citrin-deficient patients attain normal growth and prevent the onset of CTLN2.
mRNA Therapy Improves Metabolic and Behavioral Abnormalities in a Murine Model of Citrin Deficiency
2019, Molecular Therapy
Citrin deficiency is an autosomal recessive disorder caused by loss-of-function mutations in SLC25A13, encoding the liver-specific mitochondrial aspartate/glutamate transporter. It has a broad spectrum of clinical phenotypes, including life-threatening neurological complications. Conventional protein replacement therapy is not an option for these patients because of drug delivery hurdles, and current gene therapy approaches (e.g., AAV) have been hampered by immunogenicity and genotoxicity. Although dietary approaches have shown some benefits in managing citrin deficiency, the only curative treatment option for these patients is liver transplantation, which is high-risk and associated with long-term complications because of chronic immunosuppression. To develop a new class of therapy for citrin deficiency, codon-optimized mRNA encoding human citrin (hCitrin) was encapsulated in lipid nanoparticles (LNPs). We demonstrate the efficacy of hCitrin-mRNA-LNP therapy in cultured human cells and in a murine model of citrin deficiency that resembles the human condition. Of note, intravenous (i.v.) administration of the hCitrin-mRNA resulted in a significant reduction in (1) hepatic citrulline and blood ammonia levels following oral sucrose challenge and (2) sucrose aversion, hallmarks of hCitrin deficiency. In conclusion, mRNA-LNP therapy could have a significant therapeutic effect on the treatment of citrin deficiency and other mitochondrial enzymopathies with limited treatment options.
Current treatment for citrin deficiency during NICCD and adaptation/compensation stages: Strategy to prevent CTLN2
2019, Molecular Genetics and Metabolism
Identification of the genes responsible for adult-onset type II citrullinemia (CTLN2) and citrin protein function have enhanced our understanding of citrin deficiency. Citrin deficiency is characterized by 1) neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD); 2) adaptation/compensation stage with unique food preference from childhood to adulthood; and 3) CTLN2. The treatment of NICCD aims to prevent the progression of cholestasis, and it includes medium chain triglycerides (MCT) milk and lactose-free milk, in addition to medications (e.g., vitamin K₂, lipid-soluble vitamins and ursodeoxycholic acid). Spontaneous remission around the age of one is common in NICCD, though prolonged cholestasis can lead to irreversible liver failure and may require liver transplantation. The adaptation/compensation stage (after one year of age) is characterized by the various signs and symptoms such as hypoglycemia, fatty liver, easy fatigability, weight loss, and neuropsychiatric symptoms. Some poorly-controlled patients show failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD). Diet therapy is the key in the adaptation/compensation stage. Protein- and fat-rich diet with a protein: fat: carbohydrate ratio being 15–25%: 40–50%: 30–40% along with the appropriate energy intake is recommended. The use of MCT oil and sodium pyruvate is also effective. The toxicity of carbohydrate is well known in the progression to CTLN2 if the consumption is over a long term or intense. Alcohol can also trigger CTLN2. Continuous intravenous hyperalimentation with high glucose concentration needs to be avoided. Administration of Glyceol® (an osmotic agent containing glycerol and fructose) is contraindicated. Because the intense treatment such as liver transplantation may become necessary to cure CTLN2, the effective preventative treatment during the adaptation/compensation stage is very important. At present, there is no report of a case with patients reported having the onset of CTLN2 who are on the diet therapy and under the appropriate medical support during the adaptation/compensation stage.
Oral aversion to dietary sugar, ethanol and glycerol correlates with alterations in specific hepatic metabolites in a mouse model of human citrin deficiency
2017, Molecular Genetics and Metabolism
Citation Excerpt :
Human citrin deficiency, also known as mitochondrial aspartate-glutamate carrier 2 (AGC2) deficiency, is one of the most well-characterized genetic disorders associated with a member of the large SLC25A family of mitochondrial transporter proteins [1,2]. Now an established disease entity [3], citrin deficiency is caused by mutations in SLC25A13 that result in at least two previously distinct clinical presentations: adult-onset type II citrullinemia (CTLN2) characterized by hyperammonemia [4], and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) that leads to multiple aminoacidemias, galactosemia, hypoproteinemia and jaundice [5–7]. Citrin deficiency may also lead to additional consequences throughout life including growth retardation and hypoglycemia in infancy, fatty liver, hypertriglyceridemia, pancreatitis, and hepatocellular carcinoma [8–18], while a third phenotype, abbreviated FTTDCD and defined as failure to thrive and dyslipidemia [19,20] in an otherwise healthy individual, has also been described.
Mice carrying simultaneous homozygous mutations in the genes encoding citrin, the mitochondrial aspartate-glutamate carrier 2 (AGC2) protein, and mitochondrial glycerol-3-phosphate dehydrogenase (mGPD), are a phenotypically representative model of human citrin (a.k.a., AGC2) deficiency. In this study, we investigated the voluntary oral intake and preference for sucrose, glycerol or ethanol solutions by wild-type, citrin (Ctrn)-knockout (KO), mGPD-KO, and Ctrn/mGPD double-KO mice; all substances that are known or suspected precipitating factors in the pathogenesis of human citrin deficiency. The double-KO mice showed clear suppressed intake of sucrose, consuming less with progressively higher concentrations compared to the other mice. Similar observations were made when glycerol or ethanol were given. The preference of Ctrn-KO and mGPD-KO mice varied with the different treatments; essentially no differences were observed for sucrose, while an intermediate intake or similar to that of the double-KO mice was observed for glycerol and ethanol. We next examined the hepatic glycerol 3-phosphate, citrate, citrulline, lysine, glutamate and adenine nucleotide levels following forced enteral administration of these solutions. A strong correlation between the simultaneous increased hepatic glycerol 3-phosphate and decreased ATP or total adenine nucleotide content and observed aversion of the mice during evaluation of their voluntary preferences was found. Overall, our results suggest that the aversion observed in the double-KO mice to these solutions is initiated and/or mediated by hepatic metabolic perturbations, resulting in a behavioral response to increased hepatic cytosolic NADH and a decreased cellular adenine nucleotide pool. These findings may underlie the dietary predilections observed in human citrin deficient patients.
Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment
2017, Molecular Genetics and Metabolism
Citrin deficiency causes adult-onset type II citrullinemia (CTLN-2), which later manifests as severe liver steatosis and life-threatening encephalopathy. Long-standing energy deficit of the liver and brain may predispose ones to CTLN-2. Here, we compared the energy-driving tricarboxylic acid (TCA) cycle and fatty acid β-oxidation cycle between 22 citrin-deficient children (age, 3–13 years) with normal liver functions and 37 healthy controls (age, 5–13 years). TCA cycle analysis showed that basal plasma citrate and α-ketoglutarate levels were significantly higher in the affected than the control group (p < 0.01). Conversely, basal plasma fumarate and malate levels were significantly lower than those for the control (p < 0.001). The plasma level of 3-OH-butyrate derived from fatty acid β-oxidation was significantly higher in the affected group (p < 0.01). Ten patients underwent sodium pyruvate therapy. However, this therapy did not correct or attenuate such deviations in both cycles. Sodium pyruvate therapy significantly increased fasting insulin secretion (p < 0.01); the fasting sugar level remained unchanged. Our results suggest that citrin-deficient children show considerable deviations of TCA cycle metabolite profiles that are resistant to sodium pyruvate treatment. Thus, long-standing and considerable TCA cycle dysfunction might be a pivotal metabolic background of CTLN-2 development.
Mechanism for increased hepatic glycerol synthesis in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse: Urine glycerol and glycerol 3-phosphate as potential diagnostic markers of human citrin deficiency
2015, Biochimica et Biophysica Acta - Molecular Basis of Disease
The mitochondrial aspartate-glutamate carrier isoform 2 (citrin) and mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) double-knockout mouse has been a useful model of human citrin deficiency. One of the most prominent findings has been markedly increased hepatic glycerol 3-phosphate (G3P) following oral administration of a sucrose solution. We aimed to investigate whether this change is detectable outside of the liver, and to explore the mechanism underlying the increased hepatic G3P in these mice. We measured G3P and its metabolite glycerol in plasma and urine of the mice under various conditions. Glycerol synthesis from fructose was also studied using the liver perfusion system. The citrin/mGPD double-knockout mice showed increased urine G3P and glycerol under normal, fed conditions. We also found increased plasma glycerol under fasted conditions, while oral administration of different carbohydrates or ethanol led to substantially increased plasma glycerol. Fructose infusion to the perfused liver of the double-knockout mice augmented hepatic glycerol synthesis, and was accompanied by a concomitant increase in the lactate/pyruvate (L/P) ratio. Co-infusion of either pyruvate or phenazine methosulfate, a cytosolic oxidant, with fructose corrected the high L/P ratio, leading to reduced glycerol synthesis. Overall, these findings suggest that hepatic glycerol synthesis is cytosolic NADH/NAD⁺ ratio-dependent and reveal a likely regulatory mechanism for hepatic glycerol synthesis following a high carbohydrate load in citrin-deficient patients. Therefore, urine G3P and glycerol may represent potential diagnostic markers for human citrin deficiency.

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^☆: Reprint requests: Takeshi Tomomasa, MD, Department of Pediatrics, Gunma University School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan.

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Clinical and Laboratory ObservationsPossible clinical and histologic manifestations of adult-onset type II citrullinemia in early infancy☆

Abstract

Section snippets

Case 1

Case 2

Discussion

Hereditary disorders of the urea cycle in man: biochemical and molecular approaches

Rev Physiol Biochem Pharmacol

Urea cycle enzymes

Type II citrullinemia (citrin deficiency): a mysterious disease caused by a defect of calcium-binding mitochondrial carrier protein

Pancreatic secretory trypsin inhibitor as a diagnostic marker for adult-onset type II citrullinemia

Hepatology

Clinical and Laboratory Observations
Possible clinical and histologic manifestations of adult-onset type II citrullinemia in early infancy☆