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|Year : 2015 | Volume
| Issue : 2 | Page : 220-222
Citrin deficiency: A treatable cause of acute psychosis in adults
Sunita Bijarnia-Mahay1, Johannes Häberle2, Véronique Rüfenacht2, Yosuke Shigematsu3, Renu Saxena1, Ishwar C Verma1
1 Center of Medical Genetics, Sir Ganga Ram Hospital, New Delhi, India
2 Division of Metabolism, University Children's Hospital, Zurich, Switzerland
3 Department of Health Science, Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
|Date of Web Publication||5-May-2015|
Dr. Sunita Bijarnia-Mahay
Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi
Source of Support: None, Conflict of Interest: None
Citrin deficiency is an autosomal recessive genetic disorder caused by a defect in the mitochondrial aspartate/glutamate antiporter, citrin. The disorder manifests either as neonatal intra-hepatic cholestasis or occurs in adulthood with recurrent hyperammonemia and neuropsychiatric disturbances. It has a high prevalence in the East Asian population, but is actually pan-ethnic. We report the case of a 26-year-old male patient presenting with episodes of abnormal neuro-psychiatric behavior associated with hyperammonemia, who was diagnosed to be having citrin deficiency. Sequencing of the SLC25A13 gene revealed two novel mutations, a single base pair deletion, c. 650delT (p.Phe217Serfs*33) in exon 7, and a missense mutation, c. 869T>C (p.Ile290Thr) in exon 9. Confirmation of the diagnosis allowed establishment of the appropriate management. The latter is an essential pre-requisite for obtaining a good prognosis as well as for family counseling.
Keywords: Citrin deficiency; hyperammonemia; India; organic psychosis; SLC25A13 gene
|How to cite this article:|
Bijarnia-Mahay S, Häberle J, Rüfenacht V, Shigematsu Y, Saxena R, Verma IC. Citrin deficiency: A treatable cause of acute psychosis in adults. Neurol India 2015;63:220-2
|How to cite this URL:|
Bijarnia-Mahay S, Häberle J, Rüfenacht V, Shigematsu Y, Saxena R, Verma IC. Citrin deficiency: A treatable cause of acute psychosis in adults. Neurol India [serial online] 2015 [cited 2020 Dec 4];63:220-2. Available from: https://www.neurologyindia.com/text.asp?2015/63/2/220/156285
| » Introduction|| |
Citrin deficiency (CTLN2) is an autosomal recessive inherited disorder caused by a defect in the mitochondrial aspartate/glutamate antiporter, citrin, encoded by the SLC25A13 gene.  It manifests as three clinical phenotypes: (i) Neonatal intra-hepatic cholestasis (neonatal intra-hepatic cholestasis due to citrin deficiency, NICCD); (ii) adult form with recurrent hyperammonemia and neuropsychiatric manifestations (citrullinemia type 2, CTLN2); and (iii) childhood form with failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD). 
The citrin transporter (the liver-type aspartate-glutamate carrier isoform 2) plays a role in various metabolic pathways including the aerobic glycolysis, gluconeogenesis, urea cycle and synthesis of proteins and nucleotides. ,, Its main role is to transport aspartate from the mitochondria into the cytosol in exchange for glutamate. , This leads to impairment of ureagenesis as aspartate, being a substrate of argininosuccinate synthetase, is lacking, resulting in the accumulation of citrulline as well as ammonia.
Citrin deficiency was first described in patients from Japan, where its prevalence is very high.  The estimated frequencies of SLC25A13 homozygotes reported by Lu et al. were one in 17,000 in China, one in 19,000 in Japan and one in 50,000 in Korea.  However, cases have also been reported from Vietnam, Israel, the Czech Republic, United States and England.  So far, no report from India or of an Indian origin patient has been published. Adult patients often manifest symptoms related to this deficiency after an intake of alcohol and sugar, an intake of medication, and/or after undergoing surgery. We report the case of a 26-year-old male patient presenting with episodes of acute abnormal neuropsychiatric behavior associated with hyperammonemia and confirmed to be having citrin deficiency by molecular genetic studies.
| » Case Report|| |
A 26-year-old male patient presented to the emergency department with acute drowsiness and frequent episodes of bizarre behavior since 6 weeks. The initial episode started with excessive lethargy and sleepiness. During this episode, he showed a bizarre behavior, including delirium, and an inappropriate laughter and aggression. No triggering factor, in particular fever, trauma, stress or intoxication, could be recognized. The episodes of abnormal neuropsychiatric behavior became recurrent with a waxing and waning pattern. During one of the episodes, generalized tonic-clonic seizures occurred with delirium and he was hospitalized at his native place in West Bengal. When he developed a further depression in sensorium, he was shifted to a tertiary care center. Electroencephalography (EEG) at that time showed generalized discharges and excessive delta wave activity, but his brain computed tomography and magnetic resonance imaging scans were normal, as were his electrocardiogram, chest radiograph, abdominal ultrasound and routine complete blood count, liver and renal function tests, electrolytes, and glucose and thyroid hormone estimation. The urine porphyrins were negative. The cerebrospinal fluid study was negative for infection. Plasma ammonia performed after all the above tests was 298 µmol/L (normal <35). He was then referred to our center for further evaluation and management.
On admission, his vital parameters were maintained but his sensorium was depressed; bilaterally constricted but equal-sized pupils were noted with no focal neurological deficit. Muscle tone and reflexes were normal in all four limbs. The rest of the clinical examination was unremarkable.
On further search to determine the cause of encephalopathy, the liver-related investigations, including viral markers and tests for Wilson's disease, were normal. Serum ammonia was only slightly elevated (48 µmol/L). Plasma amino acid levels were normal. On a normal diet, his general condition marginally improved.
On Day 8 of admission, the patient became drowsy and stopped responding to verbal commands. His vital signs were stable. Ammonia levels increased to 350 µmol/L. Sodium benzoate was added (250 mg/kg/day in three divided doses) to detoxify ammonia. Metabolic screening with tandem mass spectrometry revealed an elevated level of plasma citrulline (376 µmol/L; normal 6-36 µmol/L), with normal argininosuccinic acid, methionine, glutamine and arginine levels. The biochemical profile was suggestive of either citrullinemia type 1 (argininosuccinate synthetase deficiency) or a citrin deficiency, based upon the mild elevation of plasma citrulline. Molecular genetic studies were carried out by sequencing of the SLC25A13 gene. It revealed two novel heterozygous mutations: A single base pair deletion, c. 650delT (p.Phe217Serfs*33) in exon 7, and a missense mutation, c. 869T>C (p.Ile290Thr) in exon 9 [Figure 1]. While the mutation p.Phe217Serfs*33 is, in all likelihood, the disease-causing mutation due to the introduction of an early stoppage of translation, the mutation p.Ile290Thr is also predicted to be the disease causing one on in silico prediction (e.g., http://mitonet.charite.de/MutationTaster/index.html).
|Figure 1: Chromatogram showing the nucleotides surrounding the site of the two mutations found in the patient. Panels A and C show the wild type situation while panel B shows the frameshift caused by the single base pair deletion, c.650delT (p.Phe217Serfs*33) in exon 7. Panel D shows the novel heterozygous missense mutation, c.869T>C (p.Ile290Thr) in exon 9. Arrows indicate the exact position of the mutations|
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The patient's general condition gradually improved by modification of his diet and he was discharged from the hospital with the advice to take a high protein and fat diet but with a low carbohydrate content, and supplement the diet with L-arginine. Two years after the diagnosis, he remains stable with no further crisis.
| » Discussion|| |
The typical clinical features of citrin deficiency in adults include neuropsychiatric symptoms such as nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures and coma; death can result from brain edema.  These symptoms are in all likelihood, related to the raised levels of ammonia and glutamine in the brain. The typical triggering factors are changes in the diet as well as intermittent illnesses. Dietary management remains the mainstay of therapy, with the recommended regimen being restriction of carbohydrates and an increase in the protein and fat content (protein: fat: carbohydrate or PFC ratio of 19%:44%:37%), as has been recommended for the Japanese patients.  This diet, low in carbohydrate and high in protein and fat, is in contrast to the diet given in all other hyperammonemic disorders and in hepatic encephalopathy where protein restriction along with a high carbohydrate diet are the mainstay of dietary management.  Patients with citrin deficiency have an inherent fondness for protein- and fat-rich foods and have an aversion to carbohydrate-rich food. Our patient was perhaps healthy until the crisis because of his inherent dietary habits.
Liver transplantation remains the most successful therapy for citrin deficiency.  This treatment can ideally be averted by using appropriate and strict dietary precautions. Arginine supplementation is an effective way of reducing blood ammonia levels as it helps to keep the urea cycle working. Sodium pyruvate has also been tried and noted to be effective in several cases. 
The diagnosis of citrin deficiency, although rare, is important as its management is quite the opposite of that for other urea cycle disorders. Treating the hyperammonemia by a protein restriction will inevitably prove fatal in this condition.  Furthermore, many adults are admitted in the intensive care unit for encephalopathy with raised intracranial pressure (due to hyperammonemia). Under these circumstances, glycerol therapy is often given, that has proven to be detrimental to these patients.  This is because glycerol increases the NADH+/NAD ratio in the cytosol of hepatocytes, producing further metabolic derangements, leading to increased hepatocellular damage, encephalopathy and sometimes death.
This case report highlights the need to maintain a high index of suspicion in adults with an unexplained encephalopathy, with or without hyperammonemia, and to include ammonia analysis in the screening protocol because reaching an early diagnosis is of paramount importance for a good patient outcome. This is the first patient from India being reported to be having citrin deficiency, further emphasizing the fact that this disorder is truly pan-ethnic.
| » Acknowledgment|| |
The authors would like to thank Dr. Anil Arora, Senior Consultant Gastroenterologist, Sir Ganga Ram Hospital for referring the case and for assisting in the case management. The work on urea cycle disorders is supported by the Swiss National Science Foundation (grant 310030_153196 to JH).
| » References|| |
Saheki T, Kobayashi K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II Citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet 2002;47:333-41.
Kobayashi K, Saheki T, Song YZ. Citrin Deficiency. 2005 Sep 16 [Updated 2014 Jul 31]. In: Pagon RA, Adam MP, Amemiya A, Ardinder HH, Bean LJH, Bird TD, Dolan C, Fong C-T, Smith RJH, Stephens K, Wallace SE, editors. GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1181.
Saheki T, Kobayashi K, Iijima M, Nishi I, Yasuda T, Yamaguchi N, et al
. Pathogenesis and pathophysiology of citrin (a mitochondrial aspartate glutamate carrier) deficiency. Metab Brain Dis 2002;17:335-46.
Lu YB, Kobayashi K, Ushikai M, Tabata A, Iijima M, Li MX, et al
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Song YZ, Zhang ZH, Lin WX, Zhao XJ, Deng M, Ma YL, et al
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Fukushima K, Yazaki M, Nakamura M, Tanaka I, Kobayashi K, Saheki T, et al
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Kimura N, Kubo N, Narumi S, Toyoki Y, Ishido K, Kudo D, et al
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Yazaki M, Ikeda S, Kobayashi K, Saheki T. Therapeutic approaches for patients with adult-onset type II citrullinemia (CTLN2): Effectiveness of treatment with low-carbohydrate diet and sodium pyruvate. Rinsho Shinkeigaku 2010;50:844-7.
Yazaki M, Takei Y, Kobayashi K, Saheki T, Ikeda S. Risk of worsened encephalopathy after intravenous glycerol therapy in patients with adult-onset type II Citrullinemia (CTLN2). Intern Med 2005;44:188-95.
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