Longitudinal Study of Urea Cycle Disorders

Urea cycle disorders are a group of rare genetic diseases that affect how protein is broken
down in the body. UCDs are caused by a deficiency in one of six enzymes or two mitochondrial
membrane transporters responsible for removing ammonia, a waste product of protein
metabolism, from the bloodstream. Normally, ammonia is converted into urea and then removed
from the body in the form of urine. In UCDs, however, ammonia accumulates unchecked and is
not removed from the body. It then reaches the brain through the blood, where it causes
irreversible brain damage and/or death.

All UCDs, except for one (ornithine transcarbamylase deficiency), are inherited as recessive
traits. The purpose of this study is to perform a long-term analysis of a large group of
individuals with various UCDs. Biochemical status, growth, and cognitive function will be
assessed. Survival and cognitive outcome of the two most commonly used forms of treatment,
alternate pathway therapy and transplantation, will be evaluated. In addition, this study
will identify the biochemical changes that may predict future metabolic imbalances so that
they may be corrected before clinical symptoms develop.

This observational study is funded through 2019. All participants will attend an initial
study visit, which will include a medical and diet history, physical and neurological
examinations, psychological testing, and blood tests. Participants will then be followed with
subsequent study visits, which will last 2-3 hours each. Individuals with neonatal onset UCD
will be assessed every 3 months until age 2 and every 6 months thereafter. Individuals with
late onset UCD will be evaluated every 6 months. Psychological testing will take place every
2 years. Psychological testing will take from 30 minutes (for younger children) up to 3
hours, depending on test battery.

Inclusion Criteria:

- Diagnosis of NAGS deficiency, defined as the detection of a pathogenic mutation,
and/or decreased (less than 20 % of control) NAGS enzyme activity in liver ,and/or
hyperammonemia and first degree relative meets at least one of the criteria for NAGS
deficiency

- Diagnosis of CPS I deficiency, defined as decreased (less than 20 % of control) CPS I
enzyme activity in liver, and/or an identified pathogenic mutation, and/or
hyperammonemia and first degree relative meets at least one of the criteria for CPS I
deficiency

- Diagnosis of OTC deficiency, defined as the identification of a pathogenic mutation,
and/or less than 20% of control of OTC activity in the liver, and/or elevated urinary
orotate (greater than 20 uM/mM) in a random urine sample or after allopurinol
challenge test, and/or hyperammonemia and first degree relative meets at least one of
the criteria for OTC deficiency

- Diagnosis of AS deficiency (Citrullinemia), defined as a greater than or equal to
10-fold elevation of citrulline in plasma, and/or decreased AS enzyme activity in
cultured skin fibroblasts or other appropriate tissue, and/or identification of a
pathogenic mutation in the AS gene, and/or hyperammonemia and first degree relative
meets at least one of the criteria for AS Deficiency

- Diagnosis of AL deficiency (Argininosuccinic Aciduria, ASA), defined as the presence
of argininosuccinic acid in the blood or urine, and/or decreased AL enzyme activity in
cultured skin fibroblasts or other appropriate tissue, and/or identification of a
pathogenic mutation in the AL gene, and/or hyperammonemia and first degree relative
meets at least one of the criteria for AL Deficiency

- Diagnosis of ARG deficiency (Hyperargininemia), defined as a greater than or equal to
5-fold elevated arginine levels in the blood, and/or decreased arginase enzyme levels
in red blood cells or other appropriate tissue, and/or identification of a pathogenic
mutation in the ARG gene, and/or hyperammonemia and first degree relative meets at
least one of the criteria for ARG Deficiency

- Diagnosis of HHH Syndrome or ORNT deficiency, defined as a greater than or equal to
5-fold elevated plasma ornithine and homocitrulline levels in the urine, and/or a
pathogenic mutation, and/or less than 20% residual labeled ornithine incorporation
into protein in cultured fibroblasts, and/or hyperammonemia and first degree relative
meets at least one of the criteria for HHH Syndrome or ORNT Deficiency

- Diagnosis of CITR deficiency (Citrullinemia Type II), defined as elevated citrulline
levels in the blood and a pathogenic mutation and/or hyperammonemia and first degree
relative meets criteria for CITR Deficiency

- Pending diagnosis of a UCD (UCD highly likely), defined as laboratory values highly
suggestive of a UCD with symptomatic hyperammonemic episodes but without a verifiable
diagnosis

Exclusion Criteria:

- Hyperammonemia caused by an organic academia, lysinuric protein intolerance,
mitochondrial disorder, congenital lactic academia, fatty acid oxidation defects, or
primary liver disease

- Rare and unrelated comorbidities (e.g., Down's syndrome, intraventricular hemorrhage
in the newborn period, and extreme prematurity)