SLC25A13 – Adult-Onset Type II Citrullinemia

Adult-onset type II citrullinemia is an autosomal recessive urea cycle disorder caused by biallelic loss-of-function variants in SLC25A13, encoding the mitochondrial aspartate/glutamate carrier citrin. Clinically, patients present in adulthood with recurrent hyperammonemia and neuropsychiatric disturbances under metabolic stress. The gene–disease relationship meets the highest ClinGen criteria based on extensive proband data, segregation in multiple families, and concordant functional studies.

Inheritance is autosomal recessive, with segregation demonstrated in consanguineous and non-consanguineous families. Case series and cohort studies have reported over 102 unrelated patients harboring pathogenic SLC25A13 variants, including 93 homozygous or compound heterozygous individuals, confirming AR inheritance and robust segregation (PMID:11153906). The most recurrent variant, c.851_855del (p.Arg284HisfsTer6), has been identified across East Asian and other populations, reflecting a founder effect in multiple ethnicities.

Functional assays support a loss-of-function mechanism. Slc25a13-knockout mice display marked deficits in mitochondrial aspartate transport, malate–aspartate shuttle activity, ureagenesis, and gluconeogenesis, mirroring key biochemical features of CTLN2 (PMID:14701727). Yeast complementation studies have confirmed that patient missense mutations abrogate carrier function, and lymphocyte protein analyses demonstrate absent or reduced citrin expression in affected individuals (PMID:23053473; PMID:17092749).

One notable discrepancy is that Slc25a13-null mice do not develop overt hyperammonemic encephalopathy despite biochemical defects, suggesting that additional genetic or environmental modifiers influence phenotypic penetrance in humans (PMID:14701727).

Integration of genetic and functional data has directly informed clinical practice. Definitive diagnosis by DNA analysis enables targeted metabolic management—dietary modification and arginine supplementation—and, in refractory cases, liver transplantation achieves sustained remission of hyperammonemia and neuropsychiatric symptoms (PMID:12132524).

Key Take-home: Biallelic SLC25A13 variants cause definitive autosomal recessive adult-onset type II citrullinemia via citrin loss-of-function, with robust genetic, segregation, and experimental evidence supporting clinical diagnosis, management, and genetic counseling.

References

• Internal medicine (Tokyo, Japan) • 2002 • Recovery from marked altered consciousness in a patient with adult-onset type II citrullinemia diagnosed by DNA analysis and treated with a living related partial liver transplantation. PMID:12132524
• Human genetics • 2000 • Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia. PMID:11153906
• Molecular and cellular biology • 2004 • Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia. PMID:14701727
• Journal of inherited metabolic disease • 2013 • Prediction of the functional effect of novel SLC25A13 variants using a S. cerevisiae model of AGC2 deficiency. PMID:23053473
• Molecular genetics and metabolism • 2007 • Novel diagnostic approach to citrin deficiency: analysis of citrin protein in lymphocytes. PMID:17092749

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