A Chinese adult onset type II citrullinaemia patient with 851del4/1638ins23 mutations in the SLC25A13 gene.

EDITOR—Classical citrullinaemia (CTLN1) is a rare metabolic disease caused by the deficiency of argininosuccinate synthetase (ASS, E.C.6.3.4.5), which usually has its onset in neonates or young infants. These patients may present with acute onset of disturbance of consciousness and hyperammonaemia. ASS activity is very low in all tissues tested and over 30 mutations of the ASS gene have been identified in about 50 CTLN1 patients. However, in Japan, many cases with adult onset type II citrullinaemia (CTLN2) have been reported. A previous study in CTLN2 showed a specific deficiency of ASS protein in the liver, but no ASS gene mutation could be found. Recently, the gene responsible for CTLN2 was identified by homozygosity mapping. This gene, SLC25A13, encodes a putative calcium dependent mitochondrial carrier protein (called citrin). A loss of organisation caused by the absence of functional citrin has been proposed to lead to the reduction of ASS protein in the liver. In this report, we present a Chinese patient with CTLN2. She was well until 40 years of age, when she underwent surgery for chronic otitis media. Chronic renal insuYciency was discovered during her stay in hospital and renal parenchymal disease was suspected. Two months later, an acute alteration of consciousness occurred with a blood ammonia level up to 269 μmol/l. Subsequent disturbances of consciousness of variable severity, ranging from coma to drowsiness, occurred once or twice a month thereafter. Some of the attacks were associated with large meals, but her condition did not improve after protein restriction. She had a peculiar fondness for eggs from early childhood. A plasma amino acid analysis showed a raised citrulline level (672.5 μmol/l, normal 25-75 μmol/l), but normal to mildly raised arginine levels (up to 390 μmol/l, normal 45-176 μmol/l). Subsequently, plasma citrulline varied greatly from 225 to 1375 μmol/l. A diagnosis of lysinuric protein intolerance was excluded by normal urinary excretion of lysine. Skin and liver biopsies were performed after informed consent. ASS activity in her skin fibroblasts was normal. Analyses of her liver biopsy specimen showed normal carbamoylphosphate synthetase, ornithine carbamoyltransferase, argininosuccinate lyase, and arginase activities. However, ASS activity, measured by the method of Su et al, was very low in her liver (0.156 U/g liver, normal 2.59±1.13 U/g liver). She had a very high serum pancreatic secretory trypsin inhibitor level (631 ng/ml, normal 5.9-22.7 ng/ml), but both abdominal echo and tumour markers, including áFP and CEA, were normal. Genomic DNA was extracted from her peripheral blood leucocytes and mutation analysis of the SLC25A13 gene was performed as described previously. The results showed that she was a compound heterozygote for 851del4 and 1638ins23 mutations (fig 1). Both mutations detected in this patient have been reported in Japan and 851del4 is actually the most common mutation in Japanese patients. 7 CTLN2 appears to be almost exclusively found in Japan, but a suspected case has been reported in a Chinese. Because Japanese and Chinese are ethnically related, it is not surprising to find a case in Taiwan. However, it is important to note that the mutations may be as common in Chinese as in Japanese if the mutations have originated from the common ancestor for Japanese and Chinese. Initial treatment of the patient consisted of a low protein diet plus sodium phenylbutyrate (Buphenyl), but she tolerated sodium phenylbutyrate poorly. Oral citrulline 6 g/day was given before the establishment of the diagnosis Figure 1 Mutation analysis of the SLC25A13 gene. Left panel: 851del4 mutation. The sizes of PCR products are 82 bp for wild type and 78 bp for mutant. Lanes 1-5 are DNA size marker, heterozygote control, normal, homozygote control, and the patient, respectively. The heterozygotes may show three bands because of the formation of a heteroduplex. Right panel: 1638ins23 mutation. The sizes are 123 bp for wild type and 146 bp for mutant. Lanes 1-4 are DNA size marker, the patient, homozygote control, and normal, respectively. 1 2 3 4 5 1 2 3 4 JMG 2001;38:e23 (http://www.jmgjnl.com/cgi/content/full/38/7/e23) 1 of 2