Citrin deficiency-The East-side story

Abstract

Citrin deficiency (CD) is a complex metabolic condition due to defects in SLC25A13 encoding citrin, an aspartate/glutamate carrier located in the mitochondrial inner membrane. The condition was first described in Japan and other East Asian countries in patients who were thought to suffer from classical citrullinemia type 1, and was therefore classified as a urea cycle disorder. With an improved understanding of its molecular basis, it became apparent that a defect of citrin is primarily affecting the malate-aspartate shuttle with however multiple secondary effects on many central metabolic pathways including glycolysis, gluconeogenesis, de novo lipogenesis and ureagenesis. In the meantime, it became also clear that CD must be considered as a global disease with patients identified in many parts of the world and affected by SLC25A13 genotypes different from those known in East Asian populations. The present short review summarizes the (hi)story of this complex metabolic condition and tries to explain the relevance of including CD as a differential diagnosis in neonates and infants with cholestasis and in (not only adult) patients with hyperammonemia of unknown origin with subsequent impact on the emergency management.

Keywords: adult citrullinemia; brain edema; cholestasis; fatty liver disease; hypercitrullinemia.

FIGURE 1

Role of citrin as part of the malate–aspartate shuttle in liver and related pathways. Simplified overview to illustrate the manifold interrelations of citrin, located at the inner mitochondrial membrane and being part of the malate–aspartate shuttle, with other metabolic pathways. Downward arrows (thick red) indicate possible impairment of the respective pathways and metabolites. CiC, citrate carrier; OAA, oxaloacetate; OGC, α‐ketoglutarate‐malate carrier; PPARα, peroxisome proliferator‐activated receptor α; PyC, pyruvate carrier. Source: Figure adapted from Hayasaka and Numakura.