Multi-omics Study in Citrin Deficiency

Multi-omics Study in Citrin Deficiency for Characterization of Disease-specific Metabolites and Biomarker Identification

Citrin deficiency (CD) is an underdiagnosed and understudied condition characterized by several distinct phenotypes: 1) neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), 2) the adaptation or silent period, 3) "failure to thrive and dyslipidemia" form of CD (FTTDCD), and 4) citrullinemia type II (CTLN2), with the latter representing the final and most severe form of the condition. There is currently no cure for CD and patients manage their symptoms with lifelong dietary intervention and regular checkups with their physicians. A major hurdle in developing effective treatments for CD is the lack of effective biomarkers that track well with disease severity or measure the effectiveness of therapeutics. The present study aims to identify robust circulating biomarkers of CD through analysis of blood samples from CD patients.

Study Overview

• Status: Active, not recruiting
• Conditions: Citrin Deficiency

Detailed Description

Citrin deficiency (CD) is an inherited autosomal recessive metabolic condition that is also a secondary urea cycle disorder caused by mutations in the SLC25A13 gene, which encodes for the mitochondrial transporter, citrin. Citrin is a key component of the mitochondrial malate-aspartate shuttle (MAS) and is responsible for moving Nicotinamide Adenine Dinucleotide (NADH) from the cytosol into the mitochondria via reducing equivalents such as malate, which drives mitochondrial respiration to produce energy in the form of adenosine triphosphate (ATP). The MAS is also critical in regulating Nicotinamide Adenine Dinucleotide (NAD+/NADH) redox balance to maintain cytosolic redox-dependent metabolic pathways such as glycolysis, gluconeogenesis, amino acid metabolism, and lipid metabolism. Citrin is also required to supply cytosolic aspartate, which is the substrate of one of the urea cycle enzymes, namely argininosuccinate synthetase 1, and thus important for the proper functioning of the urea cycle.

The clinical presentations of citrin deficiency often vary widely between patients but can generally be distinguished by distinct clinical phenotypes, which are neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) that affects infants, the "failure to thrive and dyslipidemia" form of CD (FTTDCD) in childhood, the adaptation or silent period, and citrullinemia type II (CTLN2), which represents the most severe form of the condition. While only a small percentage of CD patients develop CTLN2, the prognosis for these patients is typically poor. It is notable that all CD patients above 1 year old (post-NICCD) naturally develop a characteristic food preference that favors a diet rich in protein and fat while being low in carbohydrates. Other clinical findings observed in some CD patients include fatty liver, fatigue, hypoglycemia, and failure to thrive.

There is currently no effective cure for CD. Before the onset of CTLN2, patients are primarily managed by diet control with a low carbohydrate, high protein and high-fat diet, as well as medium chain triglyceride (MCT) supplementation. CTLN2 patients have been treated with sodium pyruvate, arginine, and MCT with limited success, with severe cases requiring liver transplantation as the only solution. There are currently no specific biomarkers that effectively track the disease progression, making it challenging to monitor how well patients are actually doing or to measure the effectiveness of therapies. Without proper management or timely medical interventions, patients may develop CTLN2.

Given the urgent and unmet need for biomarkers specific to CD, the main goal of this study is to uncover disease-specific biomarkers by analyzing blood samples collected from CD patients using both targeted and untargeted metabolomics, proteomics, lipidomics, and transcriptomics. Targeted omics will involve the analysis of cellular pathways associated with the condition, such as the MAS pathway, glycolysis, protein metabolism, de novo lipogenesis, lipolysis, gluconeogenesis, NAD+ metabolism, ureagenesis, and the glutamine synthetase pathway. Identification of such biomarkers will allow a deeper understanding of the disease pathogenesis. Importantly, these biomarkers may enable better tracking of disease progression and may help to prevent the onset of CTLN2. Finally, these biomarkers will also greatly benefit the development of effective therapeutic options for CD in clinical trials by serving as measurable endpoints.

Obtaining the necessary material from patients consists of a minimally invasive venous blood sampling taken during a regular outpatient visit and after the informed consent of the patients or caretakers.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan, 266-0007
    • Chiba Children's Hospital
  • Kumamoto, Japan, 860-8556
    • Kumamoto University Hospital
  • Yamagata, Japan, 990-9585
    • Yamagata University School of Medicine
  • Fukuoka
    • Kurume-shi, Fukuoka, Japan, 830-0011
      • Kurume University
  • Iruma
    • Saitama, Iruma, Japan, 350-0451
      • Saitama Medical University
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 230-0012
      • Saiseikai Yokohama City Eastern Hospital
  • Minato City
    • Tokyo, Minato City, Japan, 105-0003
      • Jikei University Hospital
  • Miyagi
    • Sendai, Miyagi, Japan, 980-8577
      • Tohoku University
  • Nagano
    • Matsumoto, Nagano, Japan, 390-0802
      • Shinshu University Hospital
  • Sapporo
    • Hokkaido, Sapporo, Japan, 063-0005
      • National Hospital Organisation Hokkaido Medical Center
  • Umeda
    • Osaka, Umeda, Japan, 1 Chome-2-2-600
      • Osaka Metropolitan University
• South Korea
  • Gyeongsang
    • Yangsang, Gyeongsang, South Korea, 50612
      • Pusan National University Yangsan Hospital
• Taiwan
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital
  • Taipei, Taiwan, 100
    • Taiwan University Hospital
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • University Hospitals Birmingham NHS Foundation Trust
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Women's and Children's Hospital NHF Foundation Trust
  • Bristol, United Kingdom, BS2 8BJ
    • Bristol Royal Hospital for Children
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital For Children NHS Foundation Trust
  • London, United Kingdom, NW1 2BU
    • University College London Hospital
  • Salford, United Kingdom, M6 8HD
    • Salford Royal NHS Foundation Trust
  • Sheffield, United Kingdom, S10 2TH
    • Sheffield Children's NHS Foundation Trust
  • Lancashire
    • Manchester, Lancashire, United Kingdom, M13 9WL
      • Central Manchester University Hospital NHS Foundation Trust
• United States
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Citrin deficiency (CD) is an inherited autosomal recessive metabolic condition that is also a secondary urea cycle disorder caused by mutations in the SLC25A13 gene, which encodes for the mitochondrial transporter, citrin.

Description

Inclusion Criteria for patient group:

• confirmed diagnosis of citrin deficiency

Exclusion Criteria for control group:

• any metabolic disease

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
CD patient; patients with citrin deficiency (mutation in SLC25A13 gene)
healthy control; matched controls

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
identification of biomarkers	The primary endpoint is the identification of biomarkers from CD patient-derived blood samples that are expressed at levels significantly different from matched controls.	three to five years from enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
biochemical profiles	The secondary endpoint consists in the identification of unique biochemical profiles from CD patient-derived blood samples that are significantly different from matched controls, and the correlation with clinical condition and dietary regimen.	three to five years from recruitment

Collaborators and Investigators

• Sponsor: Johannes Haeberle
• Collaborators: National Taiwan University Hospital; University College London Hospitals; Northern Care Alliance NHS Foundation Trust; Taipei Veterans General Hospital, Taiwan; University Hospital Birmingham NHS Foundation Trust; Mount Sinai Hospital, New York; Great Ormond Street Hospital for Children NHS Foundation Trust; Pusan National University Yangsan Hospital; Kumamoto University; Birmingham Women's and Children's NHS Foundation Trust; Sheffield Children's NHS Foundation Trust; Bristol Royal Hospital for Children; Kurume University; Yamagata University; Tohoku University; Saitama Medical University; Jikei University School of Medicine; Shinshu University Hospital; Saiseikai Yokohama City Eastern Hospital; Osaka Metropolitan University; Central Manchester University Hospital NHS Foundation Trust; Chiba Children's Hospital; National Hospital Organisation Hokkaido Medical Center; Citrin Foundation

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2023
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: March 19, 2025
• First Submitted That Met QC Criteria: March 19, 2025
• First Posted (Actual): March 26, 2025

Study Record Updates

• Last Update Posted (Actual): January 6, 2026
• Last Update Submitted That Met QC Criteria: January 5, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: multi-omics; citrin deficiency; biomarker identification
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Amino Acid Metabolism, Inborn Errors; Urea Cycle Disorders, Inborn; Adult-onset citrullinemia type 2
• Other Study ID Numbers: 2022-02306

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No