ONE SUBTYPE FOR EACH ENZYME
When the body digests protein, it’s broken down into amino acids. Some of these are converted into a toxic substance called ammonia, which is then converted to a non-toxic chemical (urea) in the liver. This is usually done by a process known as the urea cycle. In the urea cycle several steps must take place, each step requiring an enzyme for it to work.
Although genetically distinct, the UCDs share important features and are therefore typically considered as a group. Most UCDs are characterized by a build-up of ammonia in the blood called ‘hyperammonaemia’.
There are six different types of UCDs, so called subtypes, one for each enzyme in the urea cycle. The name of your urea cycle subtype represents the enzyme that is affected.
If you have a urea cycle disorder you are born without or with very little of one of the six enzymes that breakdown ammonia. Below you will find the names and a short description of the different UCDs.
Carbamoyl phosphate synthetase I deficiency (CPS1 deficiency) is a rare genetic disorder. It arises by a deficiency or lack of the enzyme Carbamoyl phosphate synthetase (CPS).
Without the CPS enzyme the liver cannot convert waste protein into urea as fast as normal. This can lead to high ammonia levels, particularly at times of increased protein breakdown.
Symptoms and management of CPS1 deficiency are similar to other UCDs.
CPS deficiency varies in severity and the age of onset. Symptoms of neonatal-onset CPS occur 24 to 72 hours after birth. Later-onset CPS1 deficiency usually presents in childhood.
Children with CPS1 deficiency inherit one non-working CPS gene from each parent and the diagnosis is confirmed by finding a mutation in the CPS gene.
Ornithine transcarbamylase deficiency (OTC deficiency) is a rare genetic disorder and the most common type of UCD. It arises by a deficiency or lack of the enzyme OTC.
Without the OTC enzyme the liver cannot convert waste protein into urea as fast as normal. This can lead to high ammonia levels, particularly at times of increased protein breakdown.
Symptoms and management of OTC deficiency are similar to other UCDs.
OTC deficiency varies in severity and age of onset. It is an X-linked disorder which means that the OTC gene is found on the X chromosome. Females have a pair of X chromosomes while males have one X chromosome and one Y chromosome. Since males only have one copy of genes from the X chromosome all males with OTC deficiency will have problems. Females with a mutation of the OTC gene may never have problems, because their second copy of the gene (on their second X chromosome) is normal. These females are said to be carriers. Males generally present with symptoms of OTC deficiency 24 to 72 hours after birth, but only about 25% of females are symptomatic in childhood.
The diagnosis is confirmed by finding a mutation in the OTC gene.
Argininosuccinate lyase deficiency (ASL), also called argininosuccinic aciduria (ASA), is a rare genetic disorder. It arises by a deficiency or lack of the argininosuccinate lyase enzyme (ASL).
Without the ASL enzyme the liver cannot convert waste protein into urea as fast as normal. This can lead to high ammonia levels, particularly at times of increased protein breakdown.
Symptoms and management of ASL deficiency are similar to other UCDs.
ASL deficiency varies in severity and age of onset. People with ASL may present with symptoms shortly after birth for the severe form (within 24 to 48 hours) or in childhood for partial deficiency of ASL enzyme.
Children with ASL deficiency inherit one non-working ASL gene from each parent and the diagnosis is confirmed by finding a mutation in the ASL gene.
Argininosuccinate synthetase deficiency (ASS), also called citrullinemia type 1 (CTLN1), is a rare genetic disorder. It arises by a deficiency or lack of the argininosuccinate synthetase enzyme (ASS).
Without the ASS enzyme the liver cannot convert waste protein into urea as fast as normal. This can lead to high ammonia levels, particularly at times of increased protein breakdown.
Accumulation of very high levels of citrulline distinguishes ASS deficiency from other UCDs.
Symptoms and management of ASS deficiency are similar to other UCDs. People with ASS may present with symptoms within 24 to 72 hours of birth or in childhood.
Children with ASS deficiency inherit one non-working ASS gene from each parent. The ASS gene has the instructions for making the ASS enzyme and the diagnosis is confirmed by finding the mutation in the ASS gene.
Arginase 1 deficiency (ARG1-D), also called hyperargininaemia, is a rare genetic disorder. It arises by a deficiency or lack of the arginase 1 (ARG1) enzyme.
People with ARG 1 deficiency can present with symptoms later than people with other UCDs and hyperammonaemia is not as predominant or as severe.
Affected children may get stiff legs (spasticity), learning difficulties, seizures and poor growth as result of the high arginine and ammonia levels in the blood. Usually, children with ARG 1 deficiency begin to develop gait abnormalities and spasticity at 2 to 3 years of age.
Children with Arginase 1 deficiency inherit one non-working ARG1 gene from each parent. Accumulation of high levels of plasma arginine distinguishes ARG1-D from other UCDs and the diagnosis can be confirmed by finding the mutation in the ARG1 gene and high arginine levels in the blood.
N-acetylglutamate synthase deficiency (NAGS) is a rare genetic disorder. It arises by a deficiency or lack of the N-acetylglutamate synthase enzyme (NAGS).
Without the NAGS enzyme the liver cannot convert waste protein into urea as fast as normal. This can lead to high ammonia levels, particularly at times of increased protein breakdown.
Symptoms and management of NAGS deficiency are similar to other UCDs. People with NAGS may present with symptoms within 24 to 72 hours of birth or later in life.
Children with NAGS deficiency inherit one non-working NAGS gene from each parent and the NAGS gene has the instructions for making the NAGS enzyme. The diagnosis is confirmed by finding a mutation in the NAGS gene.
Furthermore, there are two enzyme transporter deficiencies, which are also considered UCDs:
Ornithine translocase deficiency (HHH), also called hyperornithinaemia-hyperammonaemia homocitrullinuria syndrome
Citrullinaemia type 2 deficiency (CTLN2), also called citrin deficiency
THE UREA CYCLE
