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
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?
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).
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).
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).
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.
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