Citrullinemia, Type Ii, Adult-Onset

A number sign (#) is used with this entry because adult-onset type II citrullinemia, also known as citrin deficiency, is caused by homozygous or compound heterozygous mutation in the SLC25A13 gene (603859) on chromosome 7q21.

Neonatal-onset type II citrullinemia (605814) is caused by mutation in the same gene.

Classic citrullinemia (CTLN1; 215700) is a genetically distinct disorder caused by mutation in the gene encoding argininosuccinate synthetase (ASS1; 603470).

Description

Adult-onset type II citrullinemia is an autosomal recessive metabolic disorder characterized clinically by the sudden onset of various neuropsychologic symptoms such as disorientation, abnormal behavior, convulsions, and coma due to hyperammonemia. In some cases, rapid progression can lead to brain edema and death if liver transplantation is not possible. Some patients may present with nonalcoholic hepatic steatosis or may develop hepatic fibrosis or hepatocellular carcinoma. Patients with this disorder have a natural aversion to carbohydrates and favor protein, which is in contrast to protein aversion usually observed in patients with urea cycle defects (summary by Komatsu et al., 2008).

Clinical Features

In Japan a distinct late-onset form of citrullinemia was reported; see review by Walser (1983). Significant clinical abnormality had onset in childhood or not until adulthood, age 48 years in 1 case. Symptoms included enuresis, delayed menarche, insomnia, sleep reversal, nocturnal sweats and terrors, recurrent vomiting (especially at night), diarrhea, tremors, episodes of confusion after meals, lethargy, convulsions, delusions, hallucinations, and brief episodes of coma. Delayed mental and physical development was shown by some patients. Most had a peculiar fondness for beans, peas, and peanuts from early childhood and a dislike for rice, other vegetables, and sweets. Since the preferred foods are high in arginine, the dietary predilection of these patients may reflect an arginine deficiency. As the patients get older, episodic disturbances become more frequent, and bizarre behavior, including manic episodes, echolalia, and frank psychosis, appears. Citrulline concentrations in the plasma were increased. The late-onset form is apparently autosomal recessive because sibs have been affected and some of the parents have been consanguineous. Most of the reports of the late-onset form appeared in Japanese journals; see Walser (1983) for references. An exception was the report by Matsuda et al. (1976). Also see Scott-Emuakpor et al. (1972) for a similar case reported from the United States.

In the study of adult-onset type II citrullinemia in Japanese, Yasuda et al. (2000) found that the onset of serious and recurring symptoms in CTLN2 varied from age 11 to age 79, with a mean of 34.4 years. Almost all patients suffered from a sudden disturbance of consciousness associated with disorientation, restlessness, drowsiness, and coma, and most died mainly of cerebral edema within a few years of onset.

Komatsu et al. (2008) found that 17 (89%) of 19 patients with genetically confirmed CTLN2 had hepatic steatosis. Four (21%) had been diagnosed with nonalcoholic fatty liver disease before the appearance of neuropsychologic symptoms that are usually characteristic of CTLN2. Hepatic steatosis occurred in the absence of obesity or features of the metabolic syndrome; all patients were lean. Some patients showed hepatic fibrosis, suggesting progression of liver damage. Laboratory abnormalities in CTLN2 patients included citrullinemia, abnormal liver enzymes, low albumin, increased serum triglycerides, and decreased activity of argininosuccinate synthetase. CTLN2 patients had a higher frequency of pancreatitis compared to those without mutations. Increased levels of pancreatic secretory protease inhibitor (PSTI, SPINK1; 167790) were associated with citrin deficiency, which could be a useful method of distinguishing CTLN2 patients from those with nonalcoholic fatty liver disease.

Batshaw et al. (2014) reported the results of an analysis of 614 patients with urea cycle disorders (UCDs) enrolled in the Urea Cycle Disorders Consortium's longitudinal study protocol. Citrullinemia type II occurred in 2 patients (0.3%), of whom 1 had the late-onset form and the other the neonatal form.

Biochemical Features

Most patients with adult-onset citrullinemia in Japan were found to have type II citrullinemia, which is associated with decreased activity of argininosuccinate synthetase activity and protein in the liver but normal ASS1 levels in other tissues such as kidney, brain, and fibroblasts. Patients suffer from a disturbance of consciousness, such as disorientation, restlessness, and coma, and may die with cerebral edema within a few years of onset. Although there is a decrease in ASS enzyme protein with normal kinetic properties, there was no apparent abnormality in the amount, translational activity, or gross structure of hepatic ASS mRNA (Kobayashi et al., 1993).

Mapping

Kobayashi et al. (1999) studied 118 CTLN2 families in Japan and localized the CTLN2 locus to chromosome 7q21.3 by homozygosity mapping analysis of individuals from 18 consanguineous unions.

Molecular Genetics

Exclusion of Mutations in the ASS1 Gene

Kobayashi et al. (1993) found on sequence analysis no mutation in the ASS1 mRNA from 2 patients with adult-onset type II citrullinemia. They also reported RFLP analysis of a consanguineous family with type II citrullinemia in which 3 polymorphisms located within the ASS1 gene locus were examined. In spite of having consanguineous parents, the patient was not homozygous for the ASS1 gene haplotype. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 had the heterozygous pattern for 1 of the 3 DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggested that the primary defect of type II citrullinemia was not within the ASS1 gene locus.

Pathogenic Mutations in the SLC25A13 Gene

In 18 adult patients with CTLN2 from consanguineous parents, Kobayashi et al. (1999) identified 5 distinct mutations (603859.0001-603859.0005) in the SLC25A13 gene, encoding citrin, and confirmed their causative role in the disease. The studies of adult-onset type II citrullinemia in Japanese were extended by Yasuda et al. (2000), who identified 2 novel mutations in the SLC25A13 gene (see, e.g., 603859). Diagnostic analysis for the 7 known mutations in 103 CTLN2 patients diagnosed by biochemical and enzymatic studies revealed that 102 patients had 1 or 2 of the 7 mutations and 93 patients were homozygotes or compound heterozygotes. Five of 22 patients from consanguineous unions were compound heterozygotes, suggesting a high frequency of the mutated genes. The frequency of homozygotes was calculated to be more than 1 in 20,000 from carrier detection (6 in 400 individuals tested) in the Japanese population. By Western blot analysis with antihuman citrin antibody, the authors detected no cross-reactive immune materials in the liver of CTLN2 patients with any of the 7 mutations. From these findings, Yasuda et al. (2000) hypothesized that CTLN2 is caused by a complete deletion of citrin, although this did not explain the mechanism of argininosuccinate synthetase deficiency.

In a 38-year-old Pakistani man living in Europe who had episodic confusion, elevated plasma ammonia and arginine levels, citrullinemia, normal glutamine, low serine levels, and fatal hyperammonemic encephalopathy, Fiermonte et al. (2008) identified homozygosity for a mutation at a highly conserved residue in the SLC25A13 gene (R588Q; 603859.0007). The authors noted that type II citrullinemia has rarely been reported outside of East Asia but must be considered in adults presenting with hyperammonemic encephalopathy, since the management is different from the management of classic urea-cycle defects (see 311250).

Pathogenesis

Saheki and Kobayashi (2002) concluded that citrin deficiency causes 2 different phenotypes, NICCD in neonates (605814) and CTLN2 in adults, through the additional effects of genetic or environmental modifiers. Since citrin and aralar (SLC25A12; 603667) are mitochondrial aspartate glutamate carriers, the various symptoms of NICCD and CTLN2 may be caused by defective aspartate export from the mitochondria to the cytosol and defects in the malate aspartate shuttle.

Komatsu et al. (2008) hypothesized that the hepatic steatosis observed in patients with CTLN2 may result from a compensatory upregulation of the malate-citrate shuttle, which increases citrate in the cytosol, resulting in increased acetyl-CoA and an overproduction of fatty acids in hepatocytes.

Clinical Management

Saheki et al. (2010) noted that conventional treatments for hyperammonemia and brain edema, such as glycerol, are harmful in patients with CTLN2 because use of carbohydrates can exacerbate hyperammonemia. The most effective treatment for this disorder is liver transplantation, although many patients can be managed by a low-carbohydrate/high-protein diet. Use of dietary arginine or sodium pyruvate may also be potentially therapeutic.

Population Genetics

Kobayashi et al. (1999) stated that the frequency of CTLN2 in Japan is approximately 1 in 100,000.

Yasuda et al. (2000) calculated the frequency of homozygotes of SLC25A13 mutations to be more than 1 in 20,000 from carrier detection (6 in 400 individuals tested) in the Japanese population.

Among 1,315 Japanese individuals tested, Yamaguchi et al. (2002) found that 18 were carriers of an SLC25A13 mutation; this provided an estimate of minimally 1 in 21,000 for homozygotes. They referred to 2 Chinese CTLN2 patients in Taiwan and a Vietnamese neonatal-onset type II citrullinemia (NICCD) patient in Australia who had the same SLC25A13 mutations as those identified in Japanese patients.

Lu et al. (2005) estimated the frequencies of SLC25A13 homozygotes to be 1 in 19,000 in Japan, 1 in 50,000 in Korea, and 1 in 17,000 in China. Specific mutations were identified in all Asian countries tested, with the most common mutations being a 4-bp deletion (603859.0001) and a splice site mutation (603859.0002). The frequencies of SLC25A13 homozygotes in China were calculated to be 1 in 9,200 to the south of the Yangtze River and 1 in 3,500,000 to the north of the Yangtze River. The findings were consistent with the historical boundary of the Yangtze River; modern Chinese are thought to derive from 2 distinct populations, 1 originating in the Yellow River valley and the other in the Yangtze River valley, during early Neolithic times (3,000 to 7,000 years ago).

Animal Model

Slc25a13-knockout mice show reduced mitochondrial Asp transport, but have no apparent phenotype, likely due to increased hepatic activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2; 138430), which can transport NADH reducing equivalents into mitochondria. Saheki et al. (2007) found that mice with a combined disruption of the Slc25a13 and Gpd2 genes had poor growth and developed citrullinemia, hyperammonemia, hypoglycemia, and fatty liver, all features of human citrin deficiency. An altered cytosolic NADH/NAD(+) ratio was closely associated with hyperammonemia. The data indicated that the more severe phenotype present in the Slc25a13/Gpd2 double-knockout mice represents a more accurate model of human citrin deficiency than Slc25a13-knockout mice.