Correspondence

An Adult with Type 2 Citrullinemia Presenting in Europe

N Engl J Med 2008; 358:1408-1409March 27, 2008

Article

To the Editor:

Type 2 citrullinemia is an adult-onset, autosomal recessive disorder characterized by episodes of hyperammonemic encephalopathy. 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 during an episode; citrullinemia and raised arginine, normal glutamine, and low serine levels were also noted, suggesting the diagnosis of type 2 citrullinemia. Unfortunately, despite aggressive treatment, the patient died from hyperammonemic encephalopathy.

Sequencing of the patient's SLC25A13 gene revealed homozygosity for a novel point mutation, c.1763G→A (AF118838.1), which produced an Arg-to-Gln substitution at residue 588 of AGC2. Functional analysis of the mutant protein showed only about 10% of normal transport of aspartate and glutamate (Figure 1Figure 1Functional Characterization of Mutant AGC2.).

The patient's parents, who were unrelated but came from the same village in Pakistan, were heterozygous for the mutation. Some members of the extended pedigree, which contained a number of first-cousin marriages, were screened; three members of the pedigree were heterozygous for the mutant allele, and two were homozygous. Both homozygotes were well and had no detectable biochemical abnormalities. The c.1763G→A mutation was not found in 104 unrelated control chromosomes.

An arginine residue is highly conserved in the equivalent position in all mitochondrial carrier proteins and is considered to be important for substrate binding.3 The equivalent R275Q mutation in the human mitochondrial ornithine carrier 1 also abolishes transport activity and is pathogenic, causing the hyperornithinemia–hyperammonemia–homocitrullinuria syndrome.

These results directly demonstrate that a reduction in mitochondrial aspartate–glutamate transport in the liver can lead to type 2 citrullinemia. In exporting aspartate from the mitochondrion to the cytoplasm, AGC2 plays a crucial role in both urea synthesis and the transfer of reducing equivalents from the cytosol to the mitochondria through the malate–aspartate NADH shuttle.4

Recent results in AGC2 knockout mice suggest that the cytosolic redox potential may be important in the generation of hyperammonemia seen in type 2 citrullinemia.5 An increased cytosolic ratio of NADH to NAD⁺, perhaps triggered by dietary factors such as carbohydrate or alcohol intake, could lower cytosolic aspartate concentrations and precipitate hyperammonemia.

Although well recognized in East Asia, type 2 citrullinemia has rarely been reported elsewhere. It is important to consider this diagnosis in adults presenting with hyperammonemic encephalopathy, since the management of type 2 citrullinemia is very different from the management of classic urea-cycle defects. Patients with type 2 citrullinemia should not be treated with a low-protein diet or an emergency regimen that includes high amounts of carbohydrate. Given the dismal prognosis for this condition, patients should be referred for consideration of liver transplantation as soon as possible after their first presentation with metabolic decompensation.

Giuseppe Fiermonte, Pharm.D.
Università degli Studi di Bari, 70125 Bari, Italy

Derek Soon, M.A., M.R.C.P.
Abhijit Chaudhuri, Ph.D.
Queen's Hospital, Romford RM7 0AB, United Kingdom

Eleonora Paradies, Ph.D.
Università degli Studi di Bari, 70125 Bari, Italy

Philip J. Lee, D.M.
University College London Hospitals, London WC1N 3BG, United Kingdom

Steve Krywawych, Ph.D.
Great Ormond Street Hospital for Children, London WC1N 3JH, United Kingdom

Ferdinando Palmieri, M.D.
Università degli Studi di Bari, 70125 Bari, Italy
fpalm@farmbiol.uniba.it

Robin H. Lachmann, Ph.D., M.R.C.P.
University College London Hospitals, London WC1N 3BG, United Kingdom

Supported by grants from Ministero dell'Università e della Ricerca, Ministero della Salute, and Apulia Region; a contract from the European Commission (LSHM-CT-2004-503116); and a Biomedical Research Centre grant from the U.K. National Institute for Health Research.

5 References

1. 1

   Kobayashi K, Sinasac DS, Iijima M, et al. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet 1999;22:159-163
   CrossRef | Web of Science | Medline

2. 2

   Palmieri L, Pardo B, Lasorsa FM, et al. Citrin and aralar1 are Ca²⁺-stimulated aspartate/glutamate transporters in mitochondria. EMBO J 2001;20:5060-5069
   CrossRef | Web of Science | Medline

3. 3

   Robinson AJ, Kunji ER. Mitochondrial carriers in the cytoplasmic state have a common substrate binding site. Proc Natl Acad Sci U S A 2006;103:2617-2622
   CrossRef | Web of Science | Medline

4. 4

   Palmieri F. The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch 2004;447:689-709
   CrossRef | Web of Science | Medline

5. 5

   Saheki T, Iijima M, Li MX, et al. Citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mice recapitulate features of human citrin deficiency. J Biol Chem 2007;282:25041-25052
   CrossRef | Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   Giuseppe Fiermonte, Giovanni Parisi, Diego Martinelli, Francesco De Leonardis, Giuliano Torre, Ciro Leonardo Pierri, Alessia Saccari, Francesco Massimo Lasorsa, Angelo Vozza, Ferdinando Palmieri, Carlo Dionisi-Vici. (2011) A new Caucasian case of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD): A clinical, molecular, and functional study. Molecular Genetics and Metabolism 104:4, 501-506
   CrossRef

2. 2

   Stefan Bröer, Manuel Palacín. (2011) The role of amino acid transporters in inherited and acquired diseases. Biochemical Journal 436:2, 193-211
   CrossRef

3. 3

   Hui-Hui Tan, Wan-Cheng Chow, Kiat-Hon Lim, Wei-Keat Wan, Alexander Y. F. Chung, Peng-Chung Cheow, Chee-Kiat Tan. (2011) Liver Transplantation in an Adult with Citrullinaemia Type 2. Journal of Transplantation 2011, 1-4
   CrossRef

4. 4

   T. Hutchin, M. A. Preece, C. Hendriksz, A. Chakrapani, V. McClelland, F. Okumura, Y.-Z. Song, M. Iijima, K. Kobayashi, T. Saheki, P. McKiernan, U. Baumann. (2009) Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) as a cause of liver disease in infants in the UK. Journal of Inherited Metabolic Disease
   CrossRef

5. 5

   David Dimmock, Bruno Maranda, Carlo Dionisi-Vici, Jing Wang, Soledad Kleppe, Giuseppe Fiermonte, Renkui Bai, Bryan Hainline, Ada Hamosh, William E. O’Brien, Fernando Scaglia, Lee-Jun Wong. (2009) Citrin deficiency, a perplexing global disorder. Molecular Genetics and Metabolism 96:1, 44-49
   CrossRef

6. 6

   Ferdinando Palmieri. (2008) Diseases caused by defects of mitochondrial carriers: A review. Biochimica et Biophysica Acta (BBA) - Bioenergetics 1777:7-8, 564-578
   CrossRef