The status of adult patients with citrin deficiency in Japan: A report from the nation-wide study

Citrin deficiency is an autosomal recessive disorder caused by mutations in SLC25A13, encoding the inner mitochondrial membrane protein citrin. This disease manifests in age-dependent forms: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency, and adolescent and adult citrin deficiency (AACD). While NICCD often resolves with early treatment, AACD symptoms tend to persist or worsen over time. However, the long-term outcome in adult patients with citrin deficiency, particularly those affected by the symptoms of AACD, is not well understood. To address this gap, we conducted a new study from 2022 to 2024 that focused specifically on adult patients with citrin deficiency. This retrospective study investigated the long-term outcomes in a total of 128 adult patients, categorized depending on their onset of disease into NICCD, Post-NICCD, and AACD groups. Significant differences in height were observed: NICCD patients had taller median heights than AACD patients (Males: 170.6 cm vs. 168.0 cm, P = 0.016; Females: 156.0 cm vs. 153.0 cm, P = 0.007). Former NICCD patients generally achieved favorable long-term outcomes with early intervention, while AACD patients often experienced persistent or worsening symptoms, including irreversible liver damage with impaired urea cycle function. In conclusion, this study suggests that early intervention during infancy or childhood may improve long-term prognosis in citrin deficiency, particularly for NICCD patients. Conversely, outcome for AACD patients remains a concern, highlighting the need for improved management strategies in adulthood. This study emphasizes the importance of timely diagnosis and treatment to mitigate the progressive nature of citrin deficiency.