Study in Healthy Subjects, Patients With Urea Cycle Disorders (UCD) and Carriers of UCD Mutations to Evaluate Urea Cycle Function
Study in Healthy Subjects, Patients With Urea Cycle Disorders (UCD) and Carriers of UCD Mutations to Evaluate Urea Cycle Function
This diagnostic study will be performed to investigate the performance of the urea cycle in
 healthy subjects, asymptomatic carriers of Urea Cycle Disorders (UCD) mutations and subjects
 with genetically proven urea cycle disorders. The ureagenesis rate will be measured by 13C
 incorporation assay, a method for in vivo measurement of urea cycle performance with stable
 isotopes.
In this diagnostic study CCD09, the urea metabolism in UCD subjects (patients and carriers)
 and healthy subjects of different age and sex will be assessed by measurement of the
 incorporation of 13C from orally taken sodium [1,2-13C]-acetate into urea by 13C stable
 isotope ratio detection. The aim of the study is to determine the 13C urea production and to
 quantify the total urea production in healthy subject, gene defect carrier or patient as
 marker for the functioning of the urea cycle. Since there are still only few data available
 using this specific method for measurement of urea cycle performance, the aim of this study
 CCD09 is to gain additional results on the 13C assay. To this end, comparison will be made
 between 13C urea production observed in healthy subjects, UCD patients, and asymptomatic
 mutation carriers.

 An evaluation of this study may also enable the treating physician to better judge the
 severity of disease and the future risk of metabolic decompensations in patients as well as
 the potential risk for so far asymptomatic carriers.
Inclusion Criteria:

 All study groups:

 • Written informed consent given by subjects or his/her parents/legal guardians who are
 able to understand and follow instructions related to the study

 Group 1 Healthy Volunteers:

 -  Age: 18 - 65 years

 -  Healthy subjects

 -  No clinical or laboratory parameter outside normal ranges at screening and judged as
 clinically relevant by the investigator

 Group 2 Symptomatic UCD patients with genetically confirmed CPSD, OTCD, ASSD, or ASLD:

 Age: 0 - 65 years

 -  Symptomatic subjects with genetically confirmed Carbamylphosphate synthetase I
 Deficiency [CPSD], Ornithine Transcarbamylase Deficiency [OTCD], Argininosuccinate
 Synthetase Deficiency [Citrullinaemia type I], Argininosuccinate Lyase Deficiency
 [ASLD]

 -  at least 1 metabolic decompensation with clinical signs of hyperammonemia in medical
 history or genetically confirmed and prospectively treated siblings of symptomatic
 patients, even without clinical symptoms

 -  Confirmed diagnosis and medical history available (in particular number and severity
 of metabolic crises)

 Group 3 Asymptomatic carriers of UCD mutations:

 -  Age: 0 - 65 years

 -  Asymptomatic carriers of mutations for Carbamylphosphate synthetase I Deficiency
 [CPSD], Ornithine Transcarbamylase Deficiency [OTCD], Argininosuccinate Synthetase
 Deficiency [Citrullinaemia type 1], Argininosuccinate Lyase Deficiency [ASLD] no
 dietary protein restriction, no intake of ammonia scavenging drugs, no known metabolic
 decompensation with clinical signs of hyperammonemia

 Group 4:

 -  Infants between 8 - 10 kg body weight Symptomatic subjects with genetically confirmed
 Carbamylphosphate synthetase I Deficiency [CPSD] Ornithine Transcarbamylase Deficiency
 [OTCD] Argininosuccinate Synthetase Deficiency [Citrullinaemia type I]
 Argininosuccinate Lyase Deficiency [ASLD] at least 1 metabolic decompensation with
 clinical signs of hyperammonemia in medical history or genetically confirmed and
 prospectively treated siblings of symptomatic patients, even without clinical symptoms

 -  Confirmed diagnosis and medical history available (in particular number and severity
 of metabolic crises

 Exclusion Criteria:

 -  Acute illness, including vomiting, fever or other sign of infection

 -  Participation in other invasive clinical trials within 30 days prior to inclusion

 -  Liver or renal disease

 -  Acute seizures

 -  Coma

 -  Bleeding disorder

 -  Blood ammonia > 100 µmol/l for patients with a urea cycle disorder and blood ammonia >
 normal for healthy probands and asymptomatic carriers

 -  Metabolic acidosis

 -  Pregnancy or lactation

 -  Body weight < 8kg

 -  Chronic somatic or psychiatric disease not related to UCD