Classic (Type 1) Citrullinemia

What types of citrullinemia are there?

There are two types of citrullinemia. The different types vary in what mutation causes the disease, but both present very similarly (Woo, Park, and Lee 2014).

Type Type 1 Type 2
Mutation ASS1 gene SLC25A13 gene
Result Argininosuccinate synthetase deficiency


Citrin deficiency

This blog will focus on type 1.

What does type 1 citrullinemia look like and who gets it?

Type 1 citrullinemia, also know as classic citrullinemia, is a disease which presents with encephalopathic symptoms in neonatal as well as late onset patients (Woo, Park, and Lee 2014). Therefore, symptoms are presented through brain malfunctions such as altered mental state, memory loss or seizures. Most patients with type 1 citrullinemia (CTLN1) are neonates, which means they are less than four weeks old. A significant amount of these young patients do not live passed the neonatal/infant period. Other symptoms such as stroke-like episodes, liver dysfunction, or cataracts can also be indicative of CTLN1, however these are more commonly found among late-onset adult patients (Woo, Park, and Lee 2014).

How does someone get this disease?

CTLN1 is an autosomal recessive disease, meaning a person can only inherit the disease if both parents are carriers for the gene (Engel, Höhne, and Häberle 2009).

What parts of metabolism are affected?

The gene that causes classic citrullinemia is a mutated gene called ASS1, which codes for an enzyme called argininosuccinate synthetase (Shaheen et al. 1994). Argininosuccinate synthetase (ASS) is an enzyme involved in the essential metabolic pathway of the urea cycle (Gao et al. 2003). Thus, if a mutation exists in the gene for the enzyme, the enzyme will not function properly and result in a disruption of the pathway involved. The urea cycle functions to remove excess nitrogen in the body through the conversion of ammonia into urea; hence the name “urea” cycle (Ibarra-González, Fernández-Lainez, and Vela-Amieva 2010).

Crystal structure of human argininosuccinate synthase in complex with its reactants aspartate and citrulline (Karlberg et al. 2008)
Crystal structure of human argininosuccinate synthase in complex with its reactants aspartate and citrulline (Karlberg et al. 2008)

What does this enzyme do?

Specifically, ASS is the third enzyme in this cycle. As an enzyme, it catalyzes a reaction where the molecules citrulline and aspartate are combined to make the product argininosuccinate (Woo, Park, and Lee 2014).

Reaction catalyzed by argininosuccinate synthetase
Reaction catalyzed by argininosuccinate synthetase

What is happening with ASS in CTLN1?

Since a mutated ASS1 gene characterizes CTLN1, the enzyme ASS will not function properly in those with the disease. Therefore, the conversion of citrulline and aspartate into argininosuccinate (as shown above) will take a very long time to occur if at all in these patients. As a result, there is a build up of citrulline and a reduction of argininosuccinate in the patient’s system. Additionally, since this specific reaction is one of many in the urea cycle, the entire urea cycle is disrupted and therefore the other reactants in the cycle (ammonia and glutamine) will accumulate in the body and the other products of the cycle (arginine and ornithine) will be reduced as well (Woo, Park, and Lee 2014).

The urea cycle
The urea cycle

Why is this bad?

The accumulation of cycle reactants and depletion of cycle products is extremely problematic. For example, an increase in ammonia concentration will lead to ammonia toxicity. This is because the urea cycle is not the only pathway in which ammonia participates. Therefore, if too much ammonia results from a disrupted urea cycle pathway, other essential pathways in the cell will be disrupted as well, leading to further consequences on the body. The consequences that result from ASS dysfunction are the symptoms one sees in patients with CTLN1, as described above.


Links to Main Pages:

Annotated Bibliography

History and Metabolic Context

Molecular Basis of the Disease State

Treatments and Disease Management

Conclusions and Proposals for Future Work

4 Replies to “Classic (Type 1) Citrullinemia”

  1. I found this article to be very informative but had some trouble understanding the section about the ASS1 gene in CTLN1. Overall this was an interesting read.

    1. Thanks for reading Jack. I think the best way to solve your confusion is by explaining the central dogma of how proteins are created from DNA. DNA strands contain information that are read by special enzymes. These special enzymes then help to create specific proteins based off what they see in the DNA. In this instance, ASS1 is the gene found in the DNA and that is what tells these reading enzymes to create a protein called Argininosuccinate synthetase (ASS). So if there is a mutation in the DNA where the ASS1 gene is located, the special enzymes will read it incorrectly and not make the ASS that is needed for the urea cycle to function properly. I hope that helps! I think I will add a little figure or section explaining the basics of how proteins are made from DNA because not everyone knows that.

  2. This disease seems really bad for infants. The article above was easy to read and understand. I like how you had a picture of the urea cycle to show the affected human system. I am confused on how CTLN1 interacts with the urea cycle to cause strokes. I liked your article and I think you did a great job.

    1. I agree Austin. It’s very sad how young the patients with this disease tend to be. Thank you very much for your compliments. I am so glad you got something out of reading this. In terms of the relationship between the urea cycle and strokes, there is not much in the literature that indicates known connections or causes. CTLN1 is a very rare cause for strokes and so there is not enough data to determine what exactly the explanation for this connection is. One thing I did find is that ornithine carbamoyltransferase (another enzyme involved in the urea cycle seen in the third figure of the title page) deficiencies present with stroke as well (Choi, Kim, Yoo 2006). Clearly there is something worth investigating here.

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