RARE DISEASE
Citrullinemia type II
Citrullinemia type II
Citrullinemia type II
Synonyms: Adult-onset citrin deficiency, Adult-onset citrullinemia type 2, Adult-onset citrullinemia type II, CTLN2, Citrullinemia type 2
Synonyms: Adult-onset citrin deficiency, Adult-onset citrullinemia type 2, Adult-onset citrullinemia type II, CTLN2, Citrullinemia type 2
Synonyms: Adult-onset citrin deficiency, Adult-onset citrullinemia type 2, Adult-onset citrullinemia type II, CTLN2, Citrullinemia type 2
Drug discovery
2
drugs
With orphan designations
Overview
Citrullinemia type II (CTLN2) is an autosomal recessive urea cycle disorder caused by SLC25A13 mutations, leading to citrin deficiency. It primarily manifests in adulthood with hyperammonemia, neuropsychiatric symptoms (delirium, seizures), and liver dysfunction. Neonatal presentations (NICCD) include cholestasis and failure to thrive. Triggers include high-carbohydrate diets, alcohol, or fasting. Biochemical hallmarks include elevated citrulline (20× normal) and mild-moderate hyperammonemia, with normal-to-high arginine levels [1][3][13].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism
Research Papers
113 drug discovery papers about Citrullinemia type II, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
113 drug discovery papers about Citrullinemia type II, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-02 | Development of a quantitative real-time PCR-based newborn screening system for citrin deficiency using dried blood spots.
Citrin deficiency is an autosomal recessive metabolic disorder caused by pathogenic variants in SLC25A13, which manifests as an age-dependent spectrum ranging from neonatal intrahepatic cholestasis (NICCD) to adolescent and adult citrin deficiency (AACD, formerly CTLN2). Early detection through newborn screening (NBS) would be a prerequisite for early treatment, but conventional NBS based on citrulline and other metabolite levels has only limited sensitivity. This study aimed to develop a simple and accurate quantitative real-time PCR (qPCR)-based newborn screening (NBS) method using dried blood spots (DBSs) as a first-tier screening test to detect the six most common SLC25A13 variants in Japan. DBS samples from 1055 healthy newborns and 19 patients with confirmed variants were analyzed. Four variants (c.674C > A, c.852_855delTATG, c.1177 + 1G > A, and c.1311 + 1G > A) were screened using the TaqMan™ SNP genotyping system, and two large insertion/deletion variants (c.1638_1660dup and c.1750_1751[insNM_138459.3:2672_24;1750 + 72_1751-4dup]) were screened using a SYBR™ Green-based qPCR system with variant-specific primers. Results of qPCR were confirmed by Sanger sequencing. In all 19 known patients with citrin deficiency, the assay correctly identified the pathogenic alleles. Among 1055 newborns, heterozygous variants were detected in 19 cases (five c.852_855delTATG, thirteen c.1177 + 1G > A, and one c.1311 + 1G > A). The overall allele frequency (0.0090) was consistent with that reported in the Japanese genome database (jMorp, 0.0102), corresponding to an estimated carrier frequency of approximately 1 in 56 individuals. The assay reliably distinguished wild-type, heterozygous, and homozygous genotypes using a single DBS punch. We established a cost-effective, rapid, and reliable qPCR-based NBS system that detects the six most prevalent SLC25A13 variants using DBSs. This method is compatible with current NBS workflows and could improve early detection and intervention for citrin deficiency in Japan and, with adaptation of the target variants, in any other (not only) East Asian population.
2024-07-18 | The therapeutic landscape of citrin deficiency.
Citrin deficiency (CD) is a recessive, liver disease caused by sequence variants in the SLC25A13 gene encoding a mitochondrial aspartate-glutamate transporter. CD manifests as different age-dependent phenotypes and affects crucial hepatic metabolic pathways including malate-aspartate-shuttle, glycolysis, gluconeogenesis, de novo lipogenesis and the tricarboxylic acid and urea cycles. Although the exact pathophysiology of CD remains unclear, impaired use of glucose and fatty acids as energy sources due to NADH shuttle defects and PPARα downregulation, respectively, indicates evident energy deficit in CD hepatocytes. The present review summarizes current trends on available and potential treatments for CD. Baseline recommendation for CD patients is dietary management, often already present as a self-selected food preference, that includes protein and fat-rich food, and avoidance of excess carbohydrates. At present, liver transplantation remains the sole curative option for severe CD cases. Our extensive literature review indicated medium-chain triglycerides (MCT) as the most widely used CD treatment in all age groups. MCT can effectively improve symptoms across disease phenotypes by rapidly supplying energy to the liver, restoring redox balance and inducing lipogenesis. In contrast, sodium pyruvate restored glycolysis and displayed initial preclinical promise, with however limited efficacy in adult CD patients. Ursodeoxycholic acid, nitrogen scavengers and L-arginine treatments effectively address specific pathophysiological aspects such as cholestasis and hyperammonemia and are commonly administered in combination with other drugs. Finally, future possibilities including restoring redox balance, amino acid supplementation, enhancing bioenergetics, improving ureagenesis and mRNA/DNA-based gene therapy are also discussed.
2024-07-16 | Pathogenesis and Management of Citrin Deficiency.
Citrin deficiency (CD) is a hereditary disorder caused by SLC25A13 mutations that manifests as neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia caused by CD (FTTDCD), and adult-onset type 2 citrullinemia (CTLN2). Citrin, an aspartate-glutamate carrier primarily expressed in the liver, is a component of the malate-aspartate shuttle, which is essential for glycolysis. Citrin-deficient hepatocytes have primary defects in glycolysis and de novo lipogenesis and exhibit secondarily downregulated PPARα, leading to impaired β-oxidation. They are unable to utilize glucose and free fatty acids as energy sources, resulting in energy deficiencies. Medium-chain triglyceride (MCT) supplements are effective for treating CD by providing energy to hepatocytes, increasing lipogenesis, and activating the malate-citrate shuttle. However, patients with CD often exhibit growth impairment and irreversible brain and/or liver damage. To improve the quality of life and prevent irreversible damage, MCT supplementation with a diet containing minimal carbohydrates is recommended promptly after the diagnosis.
2023-05-22 | Nicotinamide riboside rescues dysregulated glycolysis and fatty acid β-oxidation in a human hepatic cell model of citrin deficiency.
Citrin deficiency (CD) is an inborn error of metabolism caused by loss-of-function of the mitochondrial aspartate/glutamate transporter, CITRIN, which is involved in both the urea cycle and malate-aspartate shuttle. Patients with CD develop hepatosteatosis and hyperammonemia but there is no effective therapy for CD. Currently, there are no animal models that faithfully recapitulate the human CD phenotype. Accordingly, we generated a CITRIN knockout HepG2 cell line using Clustered Regularly Interspaced Short Palindromic Repeats/Cas 9 genome editing technology to study metabolic and cell signaling defects in CD. CITRIN KO cells showed increased ammonia accumulation, higher cytosolic ratio of reduced versus oxidized form of nicotinamide adenine dinucleotide (NAD) and reduced glycolysis. Surprisingly, these cells showed impaired fatty acid metabolism and mitochondrial activity. CITRIN KO cells also displayed increased cholesterol and bile acid metabolism resembling those observed in CD patients. Remarkably, normalizing cytosolic NADH:NAD+ ratio by nicotinamide riboside increased glycolysis and fatty acid oxidation but had no effect on the hyperammonemia suggesting the urea cycle defect was independent of the aspartate/malate shuttle defect of CD. The correction of glycolysis and fatty acid metabolism defects in CITRIN KO cells by reducing cytoplasmic NADH:NAD+ levels suggests this may be a novel strategy to treat some of the metabolic defects of CD and other mitochondrial diseases.
2023-04-20 | A hybrid procedure of living donor liver transplantation for a pediatric patient with citrin deficiency.
The application of laparoscopic procedures in the liver surgery has been growing. We herein present the first case of a pediatric patient who underwent living donor liver transplantation (LDLT) using a hybrid procedure with hand-assisted laparoscopic mobilization of the liver, subsequent explantation of the diseased liver, and implantation of the graft under direct vision. A 12-year-old girl with citrin deficiency was scheduled for LDLT with a left lobe graft. After making an 8-cm upper midline incision, a 5-mm trocar was placed at the umbilicus and the right upper abdomen. Mobilization of the right liver lobe was performed using a hand-assisted laparoscopic surgery (HALS) procedure. After the extension of the midline incision, short hepatic vein dissection, encircling the right hepatic vein and hepatic hilum dissection was performed. Explantation of the liver and subsequent implantation of the liver graft were conducted under direct vision. Since the operation, her normal activities of daily life have been maintained with a normal liver function. Subsequently, her secondary sexual characteristics have recovered without any wound-related complications. A hybrid LDLT procedure was feasible for a pediatric patient. This procedure's benefits are considered meaningful for pediatric patients as it does not disrupt the rectus muscles or nerves and achieves cosmesis.
2026-04-02 | Development of a quantitative real-time PCR-based newborn screening system for citrin deficiency using dried blood spots.
Citrin deficiency is an autosomal recessive metabolic disorder caused by pathogenic variants in SLC25A13, which manifests as an age-dependent spectrum ranging from neonatal intrahepatic cholestasis (NICCD) to adolescent and adult citrin deficiency (AACD, formerly CTLN2). Early detection through newborn screening (NBS) would be a prerequisite for early treatment, but conventional NBS based on citrulline and other metabolite levels has only limited sensitivity. This study aimed to develop a simple and accurate quantitative real-time PCR (qPCR)-based newborn screening (NBS) method using dried blood spots (DBSs) as a first-tier screening test to detect the six most common SLC25A13 variants in Japan. DBS samples from 1055 healthy newborns and 19 patients with confirmed variants were analyzed. Four variants (c.674C > A, c.852_855delTATG, c.1177 + 1G > A, and c.1311 + 1G > A) were screened using the TaqMan™ SNP genotyping system, and two large insertion/deletion variants (c.1638_1660dup and c.1750_1751[insNM_138459.3:2672_24;1750 + 72_1751-4dup]) were screened using a SYBR™ Green-based qPCR system with variant-specific primers. Results of qPCR were confirmed by Sanger sequencing. In all 19 known patients with citrin deficiency, the assay correctly identified the pathogenic alleles. Among 1055 newborns, heterozygous variants were detected in 19 cases (five c.852_855delTATG, thirteen c.1177 + 1G > A, and one c.1311 + 1G > A). The overall allele frequency (0.0090) was consistent with that reported in the Japanese genome database (jMorp, 0.0102), corresponding to an estimated carrier frequency of approximately 1 in 56 individuals. The assay reliably distinguished wild-type, heterozygous, and homozygous genotypes using a single DBS punch. We established a cost-effective, rapid, and reliable qPCR-based NBS system that detects the six most prevalent SLC25A13 variants using DBSs. This method is compatible with current NBS workflows and could improve early detection and intervention for citrin deficiency in Japan and, with adaptation of the target variants, in any other (not only) East Asian population.
2024-07-18 | The therapeutic landscape of citrin deficiency.
Citrin deficiency (CD) is a recessive, liver disease caused by sequence variants in the SLC25A13 gene encoding a mitochondrial aspartate-glutamate transporter. CD manifests as different age-dependent phenotypes and affects crucial hepatic metabolic pathways including malate-aspartate-shuttle, glycolysis, gluconeogenesis, de novo lipogenesis and the tricarboxylic acid and urea cycles. Although the exact pathophysiology of CD remains unclear, impaired use of glucose and fatty acids as energy sources due to NADH shuttle defects and PPARα downregulation, respectively, indicates evident energy deficit in CD hepatocytes. The present review summarizes current trends on available and potential treatments for CD. Baseline recommendation for CD patients is dietary management, often already present as a self-selected food preference, that includes protein and fat-rich food, and avoidance of excess carbohydrates. At present, liver transplantation remains the sole curative option for severe CD cases. Our extensive literature review indicated medium-chain triglycerides (MCT) as the most widely used CD treatment in all age groups. MCT can effectively improve symptoms across disease phenotypes by rapidly supplying energy to the liver, restoring redox balance and inducing lipogenesis. In contrast, sodium pyruvate restored glycolysis and displayed initial preclinical promise, with however limited efficacy in adult CD patients. Ursodeoxycholic acid, nitrogen scavengers and L-arginine treatments effectively address specific pathophysiological aspects such as cholestasis and hyperammonemia and are commonly administered in combination with other drugs. Finally, future possibilities including restoring redox balance, amino acid supplementation, enhancing bioenergetics, improving ureagenesis and mRNA/DNA-based gene therapy are also discussed.
2024-07-16 | Pathogenesis and Management of Citrin Deficiency.
Citrin deficiency (CD) is a hereditary disorder caused by SLC25A13 mutations that manifests as neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia caused by CD (FTTDCD), and adult-onset type 2 citrullinemia (CTLN2). Citrin, an aspartate-glutamate carrier primarily expressed in the liver, is a component of the malate-aspartate shuttle, which is essential for glycolysis. Citrin-deficient hepatocytes have primary defects in glycolysis and de novo lipogenesis and exhibit secondarily downregulated PPARα, leading to impaired β-oxidation. They are unable to utilize glucose and free fatty acids as energy sources, resulting in energy deficiencies. Medium-chain triglyceride (MCT) supplements are effective for treating CD by providing energy to hepatocytes, increasing lipogenesis, and activating the malate-citrate shuttle. However, patients with CD often exhibit growth impairment and irreversible brain and/or liver damage. To improve the quality of life and prevent irreversible damage, MCT supplementation with a diet containing minimal carbohydrates is recommended promptly after the diagnosis.
2023-05-22 | Nicotinamide riboside rescues dysregulated glycolysis and fatty acid β-oxidation in a human hepatic cell model of citrin deficiency.
Citrin deficiency (CD) is an inborn error of metabolism caused by loss-of-function of the mitochondrial aspartate/glutamate transporter, CITRIN, which is involved in both the urea cycle and malate-aspartate shuttle. Patients with CD develop hepatosteatosis and hyperammonemia but there is no effective therapy for CD. Currently, there are no animal models that faithfully recapitulate the human CD phenotype. Accordingly, we generated a CITRIN knockout HepG2 cell line using Clustered Regularly Interspaced Short Palindromic Repeats/Cas 9 genome editing technology to study metabolic and cell signaling defects in CD. CITRIN KO cells showed increased ammonia accumulation, higher cytosolic ratio of reduced versus oxidized form of nicotinamide adenine dinucleotide (NAD) and reduced glycolysis. Surprisingly, these cells showed impaired fatty acid metabolism and mitochondrial activity. CITRIN KO cells also displayed increased cholesterol and bile acid metabolism resembling those observed in CD patients. Remarkably, normalizing cytosolic NADH:NAD+ ratio by nicotinamide riboside increased glycolysis and fatty acid oxidation but had no effect on the hyperammonemia suggesting the urea cycle defect was independent of the aspartate/malate shuttle defect of CD. The correction of glycolysis and fatty acid metabolism defects in CITRIN KO cells by reducing cytoplasmic NADH:NAD+ levels suggests this may be a novel strategy to treat some of the metabolic defects of CD and other mitochondrial diseases.
2023-04-20 | A hybrid procedure of living donor liver transplantation for a pediatric patient with citrin deficiency.
The application of laparoscopic procedures in the liver surgery has been growing. We herein present the first case of a pediatric patient who underwent living donor liver transplantation (LDLT) using a hybrid procedure with hand-assisted laparoscopic mobilization of the liver, subsequent explantation of the diseased liver, and implantation of the graft under direct vision. A 12-year-old girl with citrin deficiency was scheduled for LDLT with a left lobe graft. After making an 8-cm upper midline incision, a 5-mm trocar was placed at the umbilicus and the right upper abdomen. Mobilization of the right liver lobe was performed using a hand-assisted laparoscopic surgery (HALS) procedure. After the extension of the midline incision, short hepatic vein dissection, encircling the right hepatic vein and hepatic hilum dissection was performed. Explantation of the liver and subsequent implantation of the liver graft were conducted under direct vision. Since the operation, her normal activities of daily life have been maintained with a normal liver function. Subsequently, her secondary sexual characteristics have recovered without any wound-related complications. A hybrid LDLT procedure was feasible for a pediatric patient. This procedure's benefits are considered meaningful for pediatric patients as it does not disrupt the rectus muscles or nerves and achieves cosmesis.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Citrullinemia type II.
2 orphan drug designations for Citrullinemia type II.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Heterologous human adult liver-derived progenitor cells | cell therapies | EMA | 2013-07-17 | — | Cellaion |
Glyceryl tri-(4-phenylbutyrate) | small molecules | EMA | 2010-06-10 | — | Immedica Pharma AB |
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