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Case Report
Citrin deficiency: A treatable cause of acute psychosis in adults Sunita Bijarnia‑Mahay, Johannes Häberle1, Véronique Rüfenacht1, Yosuke Shigematsu2, Renu Saxena, Ishwar C. Verma Center of Medical Genetics, Sir Ganga Ram Hospital, New Delhi, India, 1Division of Metabolism, University Children’s Hospital, Zurich, Switzerland, 2Department of Health Science, Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
ABSTRACT 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. Key words: Citrin deficiency; hyperammonemia; India; organic psychosis; SLC25A13 gene
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.[1] 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).[2] 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.[1‑3] Its main Access this article online Website: www.neurologyindia.com DOI: 10.4103/0028-3886.156285 PMID: xxxxx
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role is to transport aspartate from the mitochondria into the cytosol in exchange for glutamate.[3,4] 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.[1] 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.[4] However, cases have also been reported from Vietnam, Israel, the Czech Republic, United States and England.[5] 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
Address for correspondence: Dr. Sunita Bijarnia‑Mahay, Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India. E‑mail: [email protected]
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Neurology India / March 2015 / Volume 63 / Issue 2
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Bijarnia-Mahay, et al.: Acute Psychosis, hyperammonemia due to citrin deficiency
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
Case Report
Citrin deficiency: A treatable cause of acute psychosis in adults Sunita Bijarnia‑Mahay, Johannes Häberle1, Véronique Rüfenacht1, Yosuke Shigematsu2, Renu Saxena, Ishwar C. Verma Center of Medical Genetics, Sir Ganga Ram Hospital, New Delhi, India, 1Division of Metabolism, University Children’s Hospital, Zurich, Switzerland, 2Department of Health Science, Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
ABSTRACT 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. Key words: Citrin deficiency; hyperammonemia; India; organic psychosis; SLC25A13 gene
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.[1] 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).[2] 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.[1‑3] Its main Access this article online Website: www.neurologyindia.com DOI: 10.4103/0028-3886.156285 PMID: xxxxx
Quick Response Code
role is to transport aspartate from the mitochondria into the cytosol in exchange for glutamate.[3,4] 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.[1] 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.[4] However, cases have also been reported from Vietnam, Israel, the Czech Republic, United States and England.[5] 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
Address for correspondence: Dr. Sunita Bijarnia‑Mahay, Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India. E‑mail: [email protected]
220
Neurology India / March 2015 / Volume 63 / Issue 2
[Downloaded free from http://www.neurologyindia.com on Thursday, May 07, 2015, IP: 61.16.135.116]
Bijarnia-Mahay, et al.: Acute Psychosis, hyperammonemia due to citrin deficiency
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
