Authors' recommendations: Citrin deficiency is an inherited urea cycle disorder that has 2 well-recognized phenotypes: neonatal intrahepatic cholestasis cause by citrin deficiency (NICCD) and citrullinemia type II (CTLN2). A third intermediate phenotype has recently been proposed called failure to thrive and dyslipidemia cause by citrin deficiency (FTTDCD). NICCD is characterized by transient neonatal cholestasis (interruption in the excretion of bile), variable hepatic dysfunction, and multiple aminoacidemias in infancy. Symptoms often resolve by 1 year of age with nutritional treatment. CTLN2 is characterized by recurrent hyperammonemia and neuropsychiatric symptoms with sudden onset between 11 and 79 years of age. CTLN2 is more severe and, without treatment, can lead to death from cerebral edema within a few years of onset. The only known treatment is liver transplantation, which is remarkably effective. A preference for protein-rich and/or lipid-rich food and an aversion to carbohydrate-rich food is seen in all types of citrin deficiency. FTTDCD is characterized by these food preferences, growth retardation, and abnormalities of serum lipid concentrations. Citrin deficiency was initially thought to be limited to individuals of Japanese descent. In Japan, the prevalence of CTLN2 is 1 in 100,000 and the prevalence of NICCD is 1 in 19,000. The carrier frequency in Japan is 1 in 69. Citrin deficiency has now been observed in many world populations; however, it is most common in Asia, where the carrier frequency is 1 in 65. Citrin deficiency remains phenotypically perplexing. Citrin deficiency is an autosomal recessive condition (i.e., variants must occur on both copies of the gene in order for symptoms to be present) caused by variants in a single gene, solute carrier 25A13 (SLC25A13). SLC25A13 encodes a mitochondrial solute carrier protein named citrin. The gene was identified in 1999 and more than 50 pathogenic variants in SLC25A13 have since been identified. The inheritance of biallelic (i.e., variants on both copies of the gene) SLC25A13 variants can present as NICCD, or FTTDCD, and/or CLTN2, or with no signs or symptoms of citrin deficiency at all. Some individuals with NICCD or FTTDCD go on to develop CTLN2; however, others do not. No genotype-phenotype correlations have been made, thus it is not possible to predict the type of citrin deficiency, the age of onset, or the severity of the condition based on the specific SLC25A13 variants involved. However, when citrin deficiency is clinically or biochemically suspected, biallelic variants in the SLC25A13 gene confirm a diagnosis. This report evaluates the use of SLC25A13 genetic testing for: (a) individuals clinically or biochemically suspected to have a type of citrin deficiency; (b) neonates with a positive newborn screen suggestive of citrin deficiency; (c) asymptomatic individuals who may be at risk of developing a type of citrin deficiency based on a family history of SLC25A13 variants; (d) individuals who wish carrier testing for the purpose of reproductive planning; and (e) prenatal diagnosis of citrin deficiency in an at-risk pregnancy.

Project Status: Completed

Year Published: 2013

URL for published report: The report may be purchased from: http://www.hayesinc.com/hayes/crd/?crd=15168

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: United States

Organisation Name: HAYES, Inc.

Contact Address: 157 S. Broad Street, Suite 200, Lansdale, PA 19446, USA. Tel: 215 855 0615; Fax: 215 855 5218

Contact Name: saleinfo@hayesinc.com

Contact Email: saleinfo@hayesinc.com

Copyright: 2013 Winifred S. Hayes, Inc