Deep phenotyping of patients with citrin deficiency in Singapore- single centre experience

Citrin deficiency (CD) is a pan-ethnic autosomal recessive inborn error of metabolism due to-pathogenic variants in the SLC25A13 gene which results in disruptions of multiple metabolic pathways including glycolysis, gluconeogenesis, lipogenesis, the urea cycle, and tricarboxylic cycle.

A retrospective observational study of CD patients managed according to standard clinical practice at a single centre in Singapore (KK Women's and Children's Hospital, KKH) was undertaken from August 2016-August 2024. We present the largest cohort of patients reported in Southeast Asia focusing on clinical, biochemical and imaging findings at diagnosis, and long-term outcomes/management (including drug therapy, food preferences/adherence, hospital admissions, growth, neurodevelopmental, biochemical, and imaging outcomes). We also explore the utility of newborn screening (NBS) as a means for early detection of CD.

Eighteen CD patients (9 males; 2 sibling pairs) majority of Chinese ethnicity (n = 16) with a median duration of follow up 5 years 5 months, participated in this study. Median age at first presentation and at diagnosis was 50 days and 82 days, respectively. Fourteen patients presented with neonatal intrahepatic cholestasis caused by CD (NICCD), 2 asymptomatic from sibling screens, and two from abnormalities on NBS (one presenting with unconjugated hyperbilirubinaemia and the other with cholestasis and liver failure). Two patients had liver failure (one from NICCD group and another from NBS group). None required liver transplantation. All symptomatic patients had raised citrulline and threonine-serine ratios at presentation. None of the patients was prescribed any regular concomitant medications except for MCT oil. No genotype phenotype correlation was observed. At final assessment, all patients showed normalisation of liver parameter, galactose and plasma amino acids. Abnormalities in lipid profile in 9 patients (age 5-16 years) showed borderline high total cholesterol (median 5.4 mmol/L) and LDL (median 3.0 mmol/L) which was on the higher end of the normal range. Sixty-six percent of patients liver imaging findings were normal or showed stable changes. Food preferences (assessed in ≥1-year olds) did not reflect a clear bias towards high protein/fat diet. Adherence appeared to improve with a more prescriptive approach, it waned with age (more so in dietary aspects versus the use of MCT oil). Hospital admissions were few (median 1/patient) and unrelated to CD. Overall improvements were seen in weight, height and BMI for age z-scores, showing median weight/height/BMI for age z-scores to be -0.72, -0.83, 0.08, respectively. None had neurodevelopmental concerns.

CD remains challenging to diagnose biochemically at all ages. Current NBS strategies require further refining to increase pick up rates of CD. Cascade screening utilising genetic testing is recommended due to the presence of phenotypic heterogeneity among patients with the same genotype. However, in the absence of available genetic testing, CD should be considered in all children presenting with prolonged conjugated hyperbilirubinaemia in the presence of elevated ALP, total galactose, with/without transaminitis and typical PAA profile. With our standard treatment for CD, we observed: (i) normalisation of biochemical parameters, (ii) normalisation/stabilisation of liver imaging findings, (iii) improvements in weight/height/BMI for age scores. Adoption of a prescriptive approach appeared to encourage treatment adherence.

This retrospective study examines 18 patients with citrin deficiency at KK Women's and Children's Hospital in Singapore, the largest cohort reported in Southeast Asia. The study assesses clinical, biochemical, imaging findings, and outcome measures. Results showed improvements in growth, biochemical normalisation, and stable liver imaging with standard treatment (dietary adjustments and MCT oil). While NBS detected some cases, there remains a need for better screening strategies. This study also demonstrated a lack of genotype-phenotype correlation, suggesting that cascade screening utilising genetic testing are crucial for early diagnosis.