Clinical trial NCT06895746: Multi-omics Study in Citrin Deficiency
Official title: Multi-omics Study in Citrin Deficiency for Characterization of Disease-specific Metabolites and Biomarker Identification
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Citrin Deficiency
Keywords: citrin deficiency
multi-omics
biomarker identification
Lead sponsor: University Children's Hospital, Zurich
Sponsor class: OTHER
Collaborators: name: Citrin Foundation
name: Bristol Royal Hospital for Children
name: Central Manchester University Hospital NHS Foundation Trust
name: University Hospital Birmingham NHS Foundation Trust
name: Northern Care Alliance NHS Foundation Trust
name: Mount Sinai Hospital, New York
name: National Taiwan University Hospital
name: Taipei Veterans General Hospital, Taiwan
name: Pusan National University Yangsan Hospital
name: Saitama Medical University
name: Osaka Metropolitan University
name: Tohoku University
name: Kurume University
name: University College London Hospitals
name: Sheffield Children's NHS Foundation Trust
name: Great Ormond Street Hospital for Children NHS Foundation Trust
name: Kumamoto University
name: Saiseikai Yokohama City Eastern Hospital
name: Jikei University School of Medicine
name: Yamagata University
name: Chiba Children's Hospital
name: Shinshu University Hospital
name: Birmingham Women's and Children's NHS Foundation Trust
name: National Hospital Organisation Hokkaido Medical Center
First posted: 2025-03-26
Enrollment: 100
Sex: ALL
Minimum age (years): 0
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
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.

Brief summary: 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.

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.

Eligibility criteria: Inclusion Criteria for patient group:

* confirmed diagnosis of citrin deficiency

Exclusion Criteria for control group:

* any metabolic disease

Primary outcomes:
measure: identification of biomarkers
timeFrame: three to five years from enrollment
Secondary outcomes:
measure: biochemical profiles
timeFrame: three to five years from recruitment
Other outcomes:
Locations:
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: Kurume-shi
country: Japan
facility: Kurume University
state: Fukuoka
city: Saitama
country: Japan
facility: Saitama Medical University
state: Iruma
city: Yokohama
country: Japan
facility: Saiseikai Yokohama City Eastern Hospital
state: Kanagawa
city: Tokyo
country: Japan
facility: Jikei University Hospital
state: Minato City
city: Sendai
country: Japan
facility: Tohoku University
state: Miyagi
city: Matsumoto
country: Japan
facility: Shinshu University Hospital
state: Nagano
city: Hokkaido
country: Japan
facility: National Hospital Organisation Hokkaido Medical Center
state: Sapporo
city: Osaka
country: Japan
facility: Osaka Metropolitan University
state: Umeda
city: Chiba
country: Japan
facility: Chiba Children's Hospital
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Yamagata City
country: Japan
facility: Yamagata University School of Medicine
city: Yangsang
country: Korea, Republic of
facility: Pusan National University Yangsan Hospital
state: Gyeongsang
city: Taipei
country: Taiwan
facility: Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Manchester
country: United Kingdom
facility: Central Manchester University Hospital NHS Foundation Trust
state: Lancashire
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
city: Birmingham
country: United Kingdom
facility: Birmingham Women's and Children's Hospital NHF Foundation Trust
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
city: London
country: United Kingdom
facility: University College London Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS foundation trust
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Children's NHS Foundation Trust
Study officials:
References: