Clinical landscape of citrin deficiency: A global perspective on a multifaceted condition

Abstract

AbstractCitrin deficiency is an autosomal recessive disorder caused by a defect of citrin resulting from mutations in SLC25A13. The clinical manifestation is very variable and comprises three types: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD: OMIM 605814), post‐NICCD including failure to thrive and dyslipidemia caused by citrin deficiency, and adult‐onset type II citrullinemia (CTLN2: OMIM 603471). Frequently, NICCD can run with a mild clinical course and manifestations may resolve in the post‐NICCD. However, a subset of patients may develop CTLN2 when they become more than 18 years old, and this condition is potentially life‐threatening. Since a combination of diet with low‐carbohydrate and high‐fat content supplemented with medium‐chain triglycerides is expected to ameliorate most manifestations and to prevent the progression to CTLN2, early detection and intervention are important and may improve long‐term outcome in patients. Moreover, infusion of high sugar solution and/or glycerol may be life‐threatening in patients with citrin deficiency, particularly CTLN2. The disease is highly prevalent in East Asian countries but is more and more recognized as a global entity. Since newborn screening for citrin deficiency has only been introduced in a few countries, the diagnosis still mainly relies on clinical suspicion followed by genetic testing or selective metabolic screening. This paper aims at describing (1) the different stages of the disease focusing on clinical aspects; (2) the current published clinical situation in East Asia, Europe, and North America; (3) current efforts in increasing awareness by establishing management guidelines and patient registries, hereby illustrating the ongoing development of a global network for this rare disease.