Citrullinemia type 2 (CTLN2) is caused by mutations in the SLC25A13 gene. The disease is inherited in an autosomal recessive manner. It may manifest in form of early-onset cholestasis or as adult-onset recurrent encephalopathy. Spontaneous resolution is the most likely outcome in case of neonatal-onset disease, but this form of CTLN2 may also progress to liver failure. Adult-onset CTLN2 is related to recurrent hyperammonemic crises. They may be life-threatening. Affected individuals usually require liver transplantation.
Presentation
Both neonatal-onset and adult-onset forms of CTLN2 have been described, but there is no definite clinical presentation associated with either one. In fact, some patients may experience minor complaints only, while others fall into coma or succumb to liver failure. CTLN2 patients may present as follows:
- Intrahepatic cholestasis with jaundice and citrullinemia are the hallmarks of neonatal-onset CTLN2. Citrullinemia may be detected on newborn screens, but it has been pointed out that a positive newborn screen is not an exclusion criterion for CTLN2: Ohura and colleagues retrospectively reviewed clinical data of 75 infants diagnosed with CTLN2, with 6 of them having citrullin concentrations within the reference range [1]. Still, all those infants developed clinical symptoms within five months of life, and most of them within two. Besides jaundice, acholic stools and failure to thrive were commonly observed. Few patients presented with hepatomegaly or increased prothrombin times [1].
- Failure to thrive and dyslipidemia caused by citrin deficiency is associated with fatigue and growth retardation, and possibly with pancreatitis [2]. This form of CTLN2 is typically diagnosed in infants or young children aged up to two years. Upon enquiry, parents may describe their children to prefer food rich in proteins or lipids and to have an aversion to carbohydrates [3]. This information is particularly important because it allows for the distinction of CTLN2 and typical urea cycle disorders, with the latter being known to cause an aversion to protein [4].
- Symptoms observed in adult-onset CTLN2 comprise recurrent confusion, abnormal behavior such as hyperactivity, irritability, and aggression, seizures, transient loss of consciousness, and coma. Episodes of encephalopathy are most likely to occur in times of physical and/or psychological stress, following excessive carbohydrate intake or alcohol consumption, infectious diseases, and surgical interventions [4]. These conditions are known to facilitate the development of symptomatic hyperammonemia, although the underlying mechanisms are not yet completely understood [5]. It is known, though, that these patients may develop cerebral edema and die of it [6]. Similar to those individuals developing CTLN2 in infancy, these patients tend to avoid carbohydrate-rich food and prefer to ingest proteins [3]. They may have a history of pancreatitis [3].
It is important to note that homozygosity for pathogenic mutations does not necessarily result in clinical disease [5].
Entire Body System
- Disability
Symptoms and Signs Clinical manifestations range from mild (eg, failure to thrive, intellectual disability, episodic hyperammonemia) to severe (eg, altered mental status, coma, death). [merckmanuals.com]
Intellectual disability is one of the main sequelae. (Source: Genetic and Rare Diseases Information Center) [treatable-id.org]
See Early Intervention for Children with Disabilities/Delays (see NW providers [3]). A dietician may work with the family to devise an optimal approach to dietary management. See Nutrition Assessment Services (see NW providers [0]). [medicalhomeportal.org]
Some people with Carpenter Syndrome have mild to severe intellectual disability. [natera.com]
Fragile X Syndrome August 28, 2018 by Peter Ciszewski Fragile X Syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. [checkrare.com]
- Fatigue
Failure to thrive and dyslipidemia caused by citrin deficiency is associated with fatigue and growth retardation, and possibly with pancreatitis. This form of CTLN2 is typically diagnosed in infants or young children aged up to two years. [symptoma.com]
[…] with purpura, convulsive seizures and methioninemia]. 61 24 Wen PQ...Li CR 24327139 2013 42 [A case of neonatal intrahepatic cholestasis caused by citrin deficiency complicated with congenital biliary atresia]. 61 24 Tong F...Yang RL 24484564 2013 43 Fatigue [malacards.org]
Some FTTDCD patients have growth retardation, hypoglycemia, hyperlipidemia, pancreatitis, fatty liver, hepatoma, and fatigue. [themedicalbiochemistrypage.org]
In rare cases, affected individuals develop other signs and symptoms in early childhood after seeming to recover from NICCD, including delayed growth, extreme tiredness (fatigue), specific food preferences (mentioned above), and abnormal amounts of fats [medlineplus.gov]
- Collapse
Citrullinemia type 1 was diagnosed by tandem mass spectrometry in a full term male neonate who presented with an acute catastrophic collapse on the 3rd day of life. [indianpediatrics.net]
- Surgical Procedure
This major surgical procedure is associated with risks, and individuals who have had a liver transplant must take medication for the rest of their lives to prevent their body from rejecting the donor liver. [newbornscreening.info]
Thirteen patients subjected to bariatric surgical procedures (12 gastric by-pass and one duodenal switch) were included, with a mean follow-up of 43,5 ± 20 (9-76) months ( table I ). [scielo.isciii.es]
Gastrointestinal
- Recurrent Vomiting
Manifestations in females with OTC deficiency range from growth failure, developmental delay, psychiatric abnormalities, and episodic (especially postpartum) hyperammonemia to a phenotype similar to that of affected males (ie, recurrent vomiting, irritability [merckmanuals.com]
Symptoms include enuresis, delayed menarche, insomnia, recurrent vomiting, tremors, episodes of confusion after meals, lethargy, hallucinations, behavioral changes, seizures, and brief episodes of coma. [accessanesthesiology.mhmedical.com]
Bavdekar Unusual Cause of Intractable Vomiting in a Young Girl Reena Jain, Nirupa Chandorkar, Dinesh Raj, Pankaj Vohra and Suvasini Sharma Propofol as a Cause of Recurrent Pancreatitis in A Child with ESRD; A Cautionary Tale Gurinder Kumar Suspected Herpes [ijppediatricsindia.in]
Liver, Gall & Pancreas
- Liver Dysfunction
NICCD is characterized by suppression of the bile flow, hepatic fibrosis, low birth weight, growth retardation, hypoproteinemia, variable liver dysfunction. [abcam.com]
Further, the protein synthesis may be affected by liver dysfunction. [journals.lww.com]
The outcome of the disease is fatal liver dysfunction and hepatic encephalopathy in the first days of life. Alternative pathway medications and protein restriction are attempted, but some cases are not controllable, needing liver transplantation. [hpbonline.org]
Clinical manifestations are highly variable and range from neonatal cholestasis and liver dysfunction in NICCD to failure to thrive and dyslipidemia in FTTDCD, and hyperammonemia with neuropsychiatric symptoms in CTLN2. [medicalhomeportal.org]
Psychiatrical
- Abnormal Behavior
CTLN2 is characterized by neuropsychiatric symptoms including abnormal behaviors, loss of memory, seizures and coma. Death can result from brain edema. Onset is sudden and usually between the ages of 20 and 50 years. [abcam.com]
The condition chiefly affects the nervous system, causing confusion, restlessness, memory loss, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. These signs and symptoms can be life-threatening. [rarediseases.org]
behavior (aggression, irritability, and hyperactivity), seizures, and coma. [orpha.net]
- Delusion
CTLN2 typically presents in adulthood with recurring neuropsychiatric symptoms associated with episodic hyperammonemia, including disorientation, irritability, delusions, delirium, seizures, and coma that can lead to death from brain edema. [genedx.com]
[…] is inherited in an autosomal recessive pattern.[1] Last updated: 7/11/2011 Adult-onset citrullinemia type II chiefly affects the nervous system, causing neuropsychiatric symptoms including nocturnal delirium, aggression, irritability, hyperactivity, delusions [rarediseases.info.nih.gov]
- Aggressive Behavior
0100738 Aggressive behavior Aggression Aggressive behaviour Aggressiveness [ more ] 0000718 Asterixis 0012164 Delirium 0031258 Delusions 0000746 Drowsiness Sleepy 0002329 Elevated hepatic transaminase High liver enzymes 0002910 Fluctuations in consciousness [rarediseases.info.nih.gov]
Neurologic
- Seizure
CTLN2 is characterized by neuropsychiatric symptoms including abnormal behaviors, loss of memory, seizures and coma. Death can result from brain edema. Onset is sudden and usually between the ages of 20 and 50 years. [abcam.com]
Whether to taper medication after a seizure-free interval Waiting until the child has been seizure free for 2 or more years has some support in the literature and is common practice; the majority of children with seizures will go into remission within [medicalhomeportal.org]
Elevated ornithine and glutamine, decreased citrulline and arginine, markedly increased urine orotate Clinical features: In males, recurrent vomiting, irritability, lethargy, hyperammonemic coma, cerebral edema, spasticity, intellectual disability, seizures [merckmanuals.com]
There are over 200 inherited disorders that are associated with seizures and prompt identification and intervention is crucial for a positive outcome. [books.google.com]
She also experienced multiple seizure episodes that required frequent hospitalizations. An MRI without contrast back in 2012 noted brain atrophy and enlargement of the ventricles, but no specific loci for seizures were found. [cureus.com]
- Encephalopathy
He suddenly died of acute exacerbation of hepatic encephalopathy with severe brain edema. [jns-journal.com]
The differential diagnosis includes autoimmune encephalitis, CNS Lupus, CJD, SSPE, HIV, paraneoplastic encephalitis, neurosyphilis, Hashimoto’s encephalopathy and metabolic encephalopathy. [academic.oup.com]
Additionally, in five patients chronic pancreatitis preceded the onset of encephalopathy. [jnnp.bmj.com]
Six patients have been also given sodium pyruvate and the frequency of attacks of encephalopathy markedly decreased in 5 of 6 patients. [read.qxmd.com]
He was diagnosed with hepatic encephalopathy. DNA analysis revealed a heterozygote mutation in Solute Carrier Family 25. [surgicalcasereports.springeropen.com]
- Irritability
The condition chiefly affects the nervous system, causing confusion, restlessness, memory loss, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. These signs and symptoms can be life-threatening. [rarediseases.org]
[…] clinically by adult onset (20 and 50 years of age), recurrent episodes of hyperammonemia and associated neuropsychiatric symptoms such as nocturnal delirium, confusion, restlessness, disorientation, drowsiness, memory loss, abnormal behavior (aggression, irritability [orpha.net]
Characteristic features include confusion, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. [treatable-id.org]
- Confusion
The condition chiefly affects the nervous system, causing confusion, restlessness, memory loss, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. These signs and symptoms can be life-threatening. [rarediseases.org]
Citrullinemia type II Disease definition A severe subtype of citrin deficiency characterized clinically by adult onset (20 and 50 years of age), recurrent episodes of hyperammonemia and associated neuropsychiatric symptoms such as nocturnal delirium, confusion [orpha.net]
Characteristic features include confusion, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. [treatable-id.org]
- Hyperactivity
The condition chiefly affects the nervous system, causing confusion, restlessness, memory loss, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. These signs and symptoms can be life-threatening. [rarediseases.org]
[…] onset (20 and 50 years of age), recurrent episodes of hyperammonemia and associated neuropsychiatric symptoms such as nocturnal delirium, confusion, restlessness, disorientation, drowsiness, memory loss, abnormal behavior (aggression, irritability, and hyperactivity [orpha.net]
Characteristic features include confusion, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. [treatable-id.org]
Workup
Newborn screens are an important tool to diagnose CTLN2 in neonates before the onset of clinical symptoms. Abnormal serum amino acid profiles should raise suspicion as to a potential metabolic disease, and CTLN2 patients have been reported to have hypercitrullinemia, hypermethioninemia, and hyperphenylalaninemia. Additionally, serum concentrations of arginine, lysine, threonine, and tyrosine may be augmented. Further studies may reveal hypoproteinemia and decreased levels of coagulation factors, findings that indicate an impairment of protein biosynthesis and liver function. Hepatic transaminases may be elevated. Due to cholestasis, serum bile acid leveles are usually increased. Hypoglycemia and hypergalactosemia have also been reported as possible features of neonatal-onset CTLN2 [1] [7].
Adults suffering from CTLN2 are usually examined due to an encephalopathic episode. Such an episode is triggered by hyperammonemia, a condition easily verified by measuring serum ammonia levels. Further metabolic anomalies detected in case of adult-onset CTLN2 resemble those described for the neonatal form of the disease.
Blood sample analyses and coagulation studies should be repeated periodically independent of the patient's age in order to anticipate any possible deterioration, progression to liver failure or life-threatening hyperammonemia.
It is important to consider that metabolic profiles of CTLN2 patients differ considerably [8]. Therefore, they may only serve as a first hint on the underlying disease. It is highly recommendable to confirm the suspected diagnosis by means of genetic analyses. Sequencing of the SLC25A13 gene allows for the identification of the causal mutation and can be achieved applying simple and rapid genetic tests [9].
Serum
- Hypertriglyceridemia
Administration of arginine: effective in decreasing blood ammonia concentration, reducing calorie/carbohydrate intake, increasing protein intake improves hypertriglyceridemia. [flipper.diff.org]
0031258 Delusions 0000746 Drowsiness Sleepy 0002329 Elevated hepatic transaminase High liver enzymes 0002910 Fluctuations in consciousness 0007159 Hallucinations Hallucination Sensory hallucination [ more ] 0000738 Hepatomegaly Enlarged liver 0002240 Hypertriglyceridemia [rarediseases.info.nih.gov]
- Hypoalbuminemia
General physical examination and all routine investigations including cerebrospinal fluid examination were normal except for hypoalbuminemia (2.9 g/dl) and mild transaminitis (AST-70 IU/l, ALT 76 IU/l) (Normal range < 40 IU/l). [academic.oup.com]
[…] consciousness 0007159 Hallucinations Hallucination Sensory hallucination [ more ] 0000738 Hepatomegaly Enlarged liver 0002240 Hypertriglyceridemia Increased plasma triglycerides Increased serum triglycerides Increased triglycerides [ more ] 0002155 Hypoalbuminemia [rarediseases.info.nih.gov]
Treatment
Infants suffering from CTLN2 are to be kept on a protein-rich, lipid-rich, low-carbohydrate diet [3]. With regards to those presenting with prolonged cholestasis, bile acids may be supplemented to facilitate the digestion and subsequent absorption of lipophilic food components. Ursodeoxycholic acid may be applied to this end [3]. Medium-chain triglyceride-enriched formulas have been recommended to support CTLN2 therapy in such cases and fat-soluble vitamins may be supplemented, too [4]. It is to be kept in mind that an impairment of liver function may give rise to a coagulopathy, and that this condition may be exacerbated by vitamin K deficiency. Further dietary restrictions may be necessary depending on the metabolic anomalies detected in individual cases, e.g, lactose-free formulas are to be fed to prevent hypergalactosemia.
As for those suffering from failure to thrive and dyslipidemia caused by citrin deficiency, dietary adjustments similar to those described for affected neonates should be made. Additional administration of sodium pyruvate may improve growth [4].
Adult CTLN2 patients often require liver transplantation [10]. To bridge the gap until a transplant becomes available, arginine and sodium pyruvate may be given. These patients should also keep to a low-carbohydrate diet. In isolated cases, adult patients could be maintained on such therapy alone and did not require liver transplantation [11].
As can be seen, management of CTLN2 differs from that of other urea cycle disorders. Patients are not to be treated with a low-protein diet and metabolic decompensation cannot be corrected administering high amounts of carbohydrates like dextrose [5] [6].
Prognosis
Neonatal-onset CTLN2 usually resolves spontaneously within the first year of life. However, disease progression to liver failure requiring liver transplantation in infancy may also occur [1]. Isolated case reports exist about patients who fell ill within the neonatal period or in infancy, and who developed recurrent encephalopathy due to citrin deficiency later on [1].
Adult-onset CTLN2 is associated with a dismal prognosis. Affected individuals are to be referred for consideration of liver transplantation as soon as possible [2].
Etiology
CTLN2 patients are homozygous or compound heterozygous for mutations in the SLC25A13 gene. This gene encodes for member 13 of the solute carrier family 25, an aspartate-glutamate carrier. This carrier localizes to mitochondria and is expressed in different cell types, but the expression of isoform 2 is largely restricted to hepatocytes. This isoform is also called citrin.
The SLC25A13 gene is located on the long arm of chromosome 7. Distinct SLC25A13 mutations have been related to the disease. In detail, 11 mutations account for 95% of the mutant alleles in Japanese patients, who make up the majority of CTLN2 patients [9]. Genotype-phenotype relations have not yet been established [4].
Epidemiology
For a long time, CTLN2 has been thought to almost exclusively affect people of East Asian ancestry. And while Japanese patients still account for the vast majority of CTLN2 patients, the disease has also been described in individuals pertaining to other ethnic groups [3] [5] [12]. Both genders may be affected. Those suffering from neonatal-onset CTLN2 manifest first symptoms within a few months of life. The patient's age at the appearance of adult-onset CTLN2 varies largely and ranges from adolescence to senility [1].
In Japan, the incidence of neonatal-onset CTLN2 has been estimated to 1 in 34,000 [13]. The frequency of homozygosity for SLC25A13 mutations is presumably higher, though: For Japan, it has been estimated to 1 in 19,000, for China to 1 in 17,000 or 25,000, for Taiwan to 1 in 38,000, and for Korea to 1 in 10,000 or 50,000 [14] [15]. The disease' incidence is assumed to be significantly lower in non-Asian countries.
Pathophysiology
SLC25A13 encodes for an aspartate-glutamate carrier mediating the exchange of aspartate for glutamate and a proton across the inner mitochondrial membrane. This carrier is involved in a variety of metabolic processes, e.g., carbohydrate, protein, and nucleotide metabolism, and the urea cycle. Therefore, CTLN2 may be classified as an urea cycle disorder. However, CTLN2 als interferes with gluconeogenesis, glycolysis, galactose metabolism, protein biosynthesis and nucleotide production, and thus, the consequences of citrin deficiency go beyond those of an urea cylce disorder. While patients may develop hyperammonemia in the course of the disease - particularly those suffering from adult-onset CTLN2 -, it is no exclusion criterion. Indeed, hyperammonemia is rarely presented in case of neonatal-onset disease [1].
Prevention
Newborn screens should be carried out to detect metabolic anomalies and, in case of positive results, those should prompt further tests to determine their cause [7] [8]. However, CTLN2 may also go unnoticed in newborn screens [16]. Affected families are therefore recommended to seek genetic counseling. In the first place, genetic analyses need to be carried out on samples obtained from an affected family member to identify the underlying SLC25A13 mutation. Targeted analyses can then be performed to identify carriers and asymptomatic homozygotes who may or may not develop the disease at a later point in time. In fact, dietary adjustments may be sufficient to prevent the onset of symptoms in as-of-yet asymptomatic homozygotes [4]. Prenatal diagnosis is feasible.
Summary
CTLN2 is a metabolic disorder resulting from mutations in the SLC25A13 gene. This gene encodes for an aspartate-glutamate carrier whose isoform 2 is also called citrin. Therefore, CTLN2 is also referred to as citrin deficiency. The clinical presentation of CTLN2 is heterogeneous and ranges from neonatal-onset cholestatic liver disease to adult-onset encephalopathy. The following terms refer to distinct forms of CTLN2 [4]:
- Neonatal intrahepatic cholestasis caused by citrin deficiency or NICCD
- Failure to thrive and dyslipidemia caused by citrin deficiency or FTTDCD
- Adult-onset recurrent hyperammonemia with neuropsychiatric symptoms
The intermediate phenotype, failure to thrive and dyslipidemia caused by citrin deficiency, has only recently been defined and is thus not considered in elder literature [2] [17]. Some authors reserve the term CTLN2 to refer to the adult-onset form of the disease [4].
Patient Information
Citrullinemia type 2 (CTLN2) is a metabolic disorder inherited in an autosomal recessive manner, i.e., only individuals who inherit defective alleles from both their parents will develop the disease. Even though CTLN2 is a hereditary disease, it is not generally apparent at birth:
- However, CTLN2 patients may develop first symptoms within their first few months of life. In this case, neonatal-onset CTLN2 is diagnosed. Affected infants suffer from cholestatic liver disease and jaundice, produce pale or clay-colored stools and grow poorly. Usually, neonatal-onset CTLN2 spontaneously resolves within the first year of life if certain dietary adjustments are made. In detail, infants are to be kept on a protein-rich, lipid-rich, low-carbohydrate diet. They may require bile acid and vitamin supplements and are possibly unable to digest lactose. If this is the case, they need to be fed a lactose-free formula.
- Other patients don't develop any symptoms until reaching the age of 1 or 2. They may then show symptoms of infantile-onset CTLN2 or, as it is also called, failure to thrive and dyslipidemia caused by citrin deficiency. Fatigue and growth retardation are the hallmarks of this form of the disease. It can usually be managed with dietary adjustments similar to those described above. Additionally, affected infants may be given sodium pyruvate to improve growth.
- Adult-onset CTLN2 is the third variant of the disease. First symptoms may appear in adolescence or adulthood and are mainly to due metabolic decompensation following physical and/or psychological stress, excessive carbohydrate intake or alcohol consumption, infectious diseases, or surgical interventions. They consist in confusion, abnormal behavior such as hyperactivity, irritability, and aggression, seizures, transient loss of consciousness, and coma. These symptoms constitute an encephalopathic episode and may return if the disease is not adequately treated. Unfortunately, liver transplantation is often the only long-term solution.
As has been mentioned above, the disease is hereditary. It is caused by mutations in the SLC25A13 gene and it is diagnosed upon the identification of such mutations. CTLN2 is usually suspected if preceding biochemical analyses reveal certain metabolic anomalies, e.g., increased serum levels of citrulline or ammonia. Because metabolic anomalies detected in CTLN2 patients may resemble those expected in case of other diseases, it is important to inform the treating physician about all symptoms observed. Seemingly negligible details such as food preferences may be important to distinguish between CTLN2 and other disorders like citrullinemia type 1.
References
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- Dimmock D, Kobayashi K, Iijima M, et al. Citrin deficiency: a novel cause of failure to thrive that responds to a high-protein, low-carbohydrate diet. Pediatrics. 2007; 119(3):e773-777.
- Dimmock D, Maranda B, Dionisi-Vici C, et al. Citrin deficiency, a perplexing global disorder. Mol Genet Metab. 2009; 96(1):44-49.
- Saheki T, Song YZ. Citrin Deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
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- Takahashi H, Kagawa T, Kobayashi K, et al. A case of adult-onset type II citrullinemia--deterioration of clinical course after infusion of hyperosmotic and high sugar solutions. Med Sci Monit. 2006; 12(2):Cs13-15.
- Naito E, Ito M, Matsuura S, et al. Type II citrullinaemia (citrin deficiency) in a neonate with hypergalactosaemia detected by mass screening. J Inherit Metab Dis. 2002; 25(1):71-76.
- Tamamori A, Fujimoto A, Okano Y, et al. Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency. Pediatr Res. 2004; 56(4):608-614.
- Kikuchi A, Arai-Ichinoi N, Sakamoto O, et al. Simple and rapid genetic testing for citrin deficiency by screening 11 prevalent mutations in SLC25A13. Mol Genet Metab. 2012; 105(4):553-558.
- Chen L, Zhao B, Shang H. Teaching NeuroImages: Reversible brain MRI lesions in adult-onset type II citrullinemia. Neurology. 2017; 89(9):e115.
- Kogure T, Kondo Y, Kakazu E, et al. Three cases of adult-onset type II citrullinemia treated with different therapies: Efficacy of sodium pyruvate and low-carbohydrate diet. Hepatol Res. 2014; 44(6):707-712.
- Ben-Shalom E, Kobayashi K, Shaag A, et al. Infantile citrullinemia caused by citrin deficiency with increased dibasic amino acids. Mol Genet Metab. 2002; 77(3):202-208.
- Shigematsu Y, Hirano S, Hata I, et al. Newborn mass screening and selective screening using electrospray tandem mass spectrometry in Japan. J Chromatogr B Analyt Technol Biomed Life Sci. 2002; 776(1):39-48.
- Kobayashi K, Bang Lu Y, Xian Li M, et al. Screening of nine SLC25A13 mutations: their frequency in patients with citrin deficiency and high carrier rates in Asian populations. Mol Genet Metab. 2003; 80(3):356-359.
- Lu YB, Kobayashi K, Ushikai M, et al. Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency. J Hum Genet. 2005; 50(7):338-346.
- Wang LY, Chen NI, Chen PW, et al. Newborn screening for citrin deficiency and carnitine uptake defect using second-tier molecular tests. BMC Med Genet. 2013; 14:24.
- Song YZ, Deng M, Chen FP, et al. Genotypic and phenotypic features of citrin deficiency: five-year experience in a Chinese pediatric center. Int J Mol Med. 2011; 28(1):33-40.