Citrin Deficiency
Conditions
Keywords
Citrin Deficiency, Adolescent and Adult Citrin Deficiency, AACD, SLC25A13, liver metabolic flux, ureagenesis, Citrin
Brief summary
Citrin is an aspartate-glutamate transporter in the liver that facilitates the urea cycle pathway for ammonia detoxification via ureagenesis. It is also thought to be involved in liver energy metabolism as a component of the malate-aspartate shuttle. The clinical presentation in patients supports the hypothesis that liver glycolytic, gluconeogenic and lipogenic functions are compromised in citrin deficiency, but none of the key hepatic pathway fluxes have been measured in patients to date. This is the first study that will examine the liver metabolic fluxes in patients with citrin deficiency. Liver metabolic functions will be examined by metabolic flux assays and biochemical measurements after application of stable isotopes 2H2O and \[U-13C6\]-fructose. Urea cycle metabolites and their enrichment after application of a stable isotope tracer 15NH4Cl will be measured to examine the liver's ability to detoxify ammonia into urea.
Interventions
OTHERliver metabolic flux
All participants will be given heavy water (2H2O, deuterium-labelled) and \[U-13C6\]-fructose orally, each followed by the collection of one blood plasma sample. Additional biochemical and clinical parameters including liver fat content by MRI, liver fibrosis and cirrhosis by ultrasound imaging and plasma biochemical profiles will be analyzed.
OTHERureagenesis capacity
urea and urea cycle metabolites and their enrichment after oral administration of a stable isotope tracer 15NH4Cl will be measured to examine the liver's ability to detoxify ammonia.
Sponsors
Citrin Foundation
Marc Hellerstein, University of Berkeley
Johannes Haeberle
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Cross-sectional observational study, non-randomised
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
for AACD patients are: * Subjects with citrin deficiency, confirmed by genetic analysis to carry pathogenic variant(s) in the SLC25A13 gene * Age from 18 years to 65 years inclusive * Male or female * Written informed consent has been given * Understands and is willing, able and likely to comply with study procedures and restrictions Inclusion criteria for healthy subjects are: * Age from 18 years to 65 years inclusive, and not more than five years younger or older than the specified paired participant from the AACD group * Same sex as the specified paired participant from the AACD group * Same ethnicity the specified paired participant from the AACD group * Written informed consent has been given * Understands and is willing, able and likely to comply with study procedures and restrictions
Exclusion criteria
for AACD patients are: * acute and chronic disease requiring treatment of any kind, other than his/her AACD * females who are pregnant or lactating or attempting to become pregnant * use of any medication which, in the opinion of the investigator, is likely to interfere with liver function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Liver metabolic flux | 5 days | Liver metabolic flux will be measured by assessing the distribution of the administered isotope tracers \[U-13C6\]-fructose and heavy water. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ureagenesis capacity | 1 day | Patients will receive an oral dose of 2 mg/kg of the 15NH4Cl tracer diluted in water. Blood will be collected at various time points up to 2 hours after tracer administration to assess the body's ability to remove ammonia. |
| adverse events | 5 days | Safety and tolerability of 2H2O, \[U-13C6\]-fructose and 15NH4Cl |
| liver fat content | 1 day | Magnetic resonance imaging of the liver for fat content |
| Liver fibrosis | 1 day | Ultrasound imaging of the liver to assess fibrosis and cirrhosis |
| Clinical symptoms | 1 day | Clinical presentation and fatigue will be measured through questionnaires |
Countries
Switzerland
Outcome results
None listed