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Citrullinemia Type 2

Citrullinemia Type II

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].

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]
  • . ( 24586645 ) Zhang Z.H....Song Y.Z. 2014 36 SLC25A13 gene analysis in citrin deficiency: sixteen novel mutations in East Asian patients, and the mutation distribution in a large pediatric cohort in China. ( 24069319 ) Song Y.Z....Saheki T. 2013 37 Fatigue[malacards.org]
  • […] novel and one recurrent mutation in the SLC25A13 gene. ( 25365849 ) Avdjieva-Tzavella DM...Tincheva RS 2014 37 Newborn screening for citrin deficiency and carnitine uptake defect using second-tier molecular tests. ( 23394329 ) Wang LY...Chien YH 2013 38 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[ghr.nlm.nih.gov]
Turkish
  • .Kobayashi K 2017 14 Citrin deficiency: A rare but important metabolic disorder to consider in infants with faltering growth and hyperbilirubinaemia. ( 28800193 ) Stapleton C...Balasubramaniam S 2017 15 p.Val452Ile mutation of the SLC25A13 gene in a Turkish[malacards.org]
  • .Kobayashi K 2017 15 Citrin deficiency: A rare but important metabolic disorder to consider in infants with faltering growth and hyperbilirubinaemia. ( 28800193 ) Stapleton C...Balasubramaniam S 2017 16 p.Val452Ile mutation of the SLC25A13 gene in a Turkish[malacards.org]
Pallor
  • Ocular abnormalities of CDG-1a include: myopia, infantile esotropia, delayed visual maturation, low vision, optic pallor, and reduced rod function on electroretinography.[pliem.co.za]
Clay-Colored Stool
  • 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.[symptoma.com]
Abnormal Behavior
  • Characteristic features include confusion, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma.[treatable-id.org]
  • behavior (aggression, irritability, and hyperactivity), seizures, and coma.[orpha.net]
  • Symptoms include yellowish skin and eyes (jaundice), low birth weight, confusion, restlessness, memory loss, low blood sugar, and abnormal behaviors. CIT II is inherited in an autosomal recessive pattern.[diseaseinfosearch.org]
  • This disease can occur at any age in life with recurrent episodes of neurological signs and symptoms such as disorientation, abnormal behaviors (aggression, irritability and hyperactivity), seizures, coma and potential death from brain edema, which are[e-enm.org]
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]
  • Manifestations of CTLN2 are recurrent hyperammonemia with neuropsychiatric symptoms including nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive[themedicalbiochemistrypage.org]
  • Citrin SCL25A13 (7q21.3)* Biochemical profile: Elevated plasma citrulline, methionine, galactose, and bilirubin Clinical features: With neonatal onset, cholestasis resolved by 3 mo With adult onset, enuresis, delayed menarche, sleep reversal, vomiting, delusions[merckmanuals.com]
  • CTLN2 : it is characterized by hyperammonemia, nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma.[flipper.diff.org]
  • […] subjects usually present with skin photosensitivity (pellagra-like skin eruption), neurological symptoms (cerebellar ataxia, spasticity, delayed motor development, trembling, headaches, and hypotonia), psychiatric symptoms (anxiety, emotional instability, delusions[pliem.co.za]
Onset at Age <20
  • An autosomal recessive disorder of the urea cycle (OMIM:603471), usually of abrupt onset between age 20 and 50, which is clinically characterised by neuropsychiatric symptoms (e.g., abnormal behaviour, loss of memory, seizures), coma and death linked[medical-dictionary.thefreedictionary.com]
Seizure
  • 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]
  • ., abnormal behaviour, loss of memory, seizures), coma and death linked to brain oedema, accompanied by a marked increase in serum and urine citrulline and ammonia.[medical-dictionary.thefreedictionary.com]
  • Characteristic features include confusion, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma.[treatable-id.org]
  • […] 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), seizures[orpha.net]
  • This disease can occur at any age in life with recurrent episodes of neurological signs and symptoms such as disorientation, abnormal behaviors (aggression, irritability and hyperactivity), seizures, coma and potential death from brain edema, which are[e-enm.org]
Irritability
  • Characteristic features include confusion, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma.[treatable-id.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]
  • This disease can occur at any age in life with recurrent episodes of neurological signs and symptoms such as disorientation, abnormal behaviors (aggression, irritability and hyperactivity), seizures, coma and potential death from brain edema, which are[e-enm.org]
  • They consist in confusion, abnormal behavior such as hyperactivity, irritability, and aggression, seizures, transient loss of consciousness, and coma.[symptoma.com]
  • For these reasons, urea cycle defects are considered individually; however, the common denominator, hyperammnemia, can manifest clinically as some or all of the following: Anorexia Irritability Heavy or rapid breathing Lethargy Vomiting Disorientation[checkorphan.org]
Confusion
  • Characteristic features include confusion, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma.[treatable-id.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]
  • Symptoms include yellowish skin and eyes (jaundice), low birth weight, confusion, restlessness, memory loss, low blood sugar, and abnormal behaviors. CIT II is inherited in an autosomal recessive pattern.[diseaseinfosearch.org]
  • It is caused by mutations in the SLC25A13 gene, which encodes the liver-specific isoform of the mitochondrial aspartate–glutamate carrier (AGC2). 1 , 2 A 38-year-old Pakistani man with episodic confusion was found to have an elevated plasma ammonia level[nejm.org]
Hyperactivity
  • Characteristic features include confusion, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma.[treatable-id.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]
  • This disease can occur at any age in life with recurrent episodes of neurological signs and symptoms such as disorientation, abnormal behaviors (aggression, irritability and hyperactivity), seizures, coma and potential death from brain edema, which are[e-enm.org]
  • They consist in confusion, abnormal behavior such as hyperactivity, irritability, and aggression, seizures, transient loss of consciousness, and coma.[symptoma.com]
  • Common features include, but are not limited to, high ammonia levels in the blood (hyperammonemia), sudden onset of abnormal behaviors (i.e. aggression, irritability, hyperactivity), disorientation, seizures, and coma.[my46.org]
Tremor
  • Neurologic Poor coordination Dysdiadchkinesia Hyptnia or hypertonia Ataxia Tremor Seizures and hypothermia Lethargy progressing t combativeness, btundatin, and coma Decorticate or decerebrate posturing Causes - Citrullinemia type 2 Prevention - Citrullinemia[checkorphan.org]
  • After discharge the plasma concentration of ammonia remained high (300–400 μg/dl) and her mental state gradually deteriorated with intermittent appearance of violent hand tremor.[jnnp.bmj.com]
  • Manifestations of CTLN2 are recurrent hyperammonemia with neuropsychiatric symptoms including nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive[themedicalbiochemistrypage.org]
  • CTLN2 : it is characterized by hyperammonemia, nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma.[flipper.diff.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].

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.

Sex distribution
Age distribution

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]:

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

Article

  1. Ohura T, Kobayashi K, Tazawa Y, et al. Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). J Inherit Metab Dis. 2007; 30(2):139-144.
  2. 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.
  3. Dimmock D, Maranda B, Dionisi-Vici C, et al. Citrin deficiency, a perplexing global disorder. Mol Genet Metab. 2009; 96(1):44-49.
  4. 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.
  5. Fiermonte G, Soon D, Chaudhuri A, et al. An adult with type 2 citrullinemia presenting in Europe. N Engl J Med. 2008; 358(13):1408-1409.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Chen L, Zhao B, Shang H. Teaching NeuroImages: Reversible brain MRI lesions in adult-onset type II citrullinemia. Neurology. 2017; 89(9):e115.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.

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Last updated: 2019-07-11 21:04