Citrin deficiency, a perplexing global disorder

Mol Genet Metab. 2009 Jan;96(1):44-9. doi: 10.1016/j.ymgme.2008.10.007. Epub 2008 Nov 25.


Citrin deficiency, caused by mutations in SLC25A13, can present with neonatal intrahepatic cholestasis or with adult onset neuropsychiatric, hepatic and pancreatic disease. Until recently, it had been thought to be found mostly in individuals of East Asian ancestry. A key diagnostic feature has been the deficient argininosuccinate synthetase (ASS) activity (E.C. in liver, with normal activity in skin fibroblasts. In this series we describe the clinical presentation of 10 patients referred to our laboratories for sequence analysis of the SCL25A13 gene, including several patients who presented with elevated citrulline on newborn screening. In addition to sequence analysis performed on all patients, ASS enzyme activity, citrulline incorporation and Western blot analysis for ASS and citrin were performed on skin fibroblasts if available. We have found 5 unreported mutations including two apparent founder mutations in three unrelated French-Canadian patients. In marked contrast to previous cases, these patients have a markedly reduced ASS activity in skin fibroblasts. The presence of citrin protein on Western blot in three of our cases reduces the sensitivity of a screening test based on protein immunoblotting. The finding of citrin mutations in patients of Arabic, Pakistani, French Canadian and Northern European origins supports the concept that citrin deficiency is a panethnic disease.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Disorders, Inborn / enzymology*
  • Amino Acid Transport Disorders, Inborn / genetics
  • Amino Acids / blood
  • Argininosuccinate Synthase / genetics
  • Argininosuccinate Synthase / metabolism
  • Cells, Cultured
  • Child, Preschool
  • Citrulline / metabolism
  • Female
  • Fibroblasts / metabolism
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Membrane Transport Proteins / deficiency*
  • Membrane Transport Proteins / genetics*
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins / deficiency*
  • Mitochondrial Proteins / genetics*
  • Mutation
  • Racial Groups / genetics*


  • Amino Acids
  • Membrane Transport Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • SLC25A13 protein, human
  • Citrulline
  • Argininosuccinate Synthase