Treatments and Disease Management

How does one treat Type 1 Citrullinemia?

The key elements to treating a patient with CTLN1 are an early diagnosis and control of both intracranial pressure and hyperammonemia (“Citrullinemia Type 1 – NORD (National Organization for Rare Disorders)” 2016). Prescribing the patient with ammonia-reducing medications such as Buphenyl, Ammonul, Ravicti, or arginine can help accomplish this (See Table 1 for structures). Hemodialysis has also been successful treatment by lowering ammonia concentrations in the body (Quinonez and Thoene 1993) Patients may also have to take multiple vitamin and calcium supplements. Dietary restrictions may also be set for the patient to limit protein intake (“Citrullinemia Type 1 – NORD (National Organization for Rare Disorders)” 2016). Liver transplants have also been reported to prolong survival in some cases (Testai and Gorelick 2010). Additionally, monitoring fluid balance is essential to controlling intracranial pressure (Quinonez and Thoene 1993). Intravenous infusion of glucose is also used as treatment in order to produce an anabolic state (Testai and Gorelick 2010).

Medication Molecule Structure
Buphenyl Sodium phenylbutyrate BBU
Ammonul Sodium phenylacetate am
Ravicti Glycerol phenylbutyrate rav
Arginine Arginine argi

Table 1: Structures of ammonia reducing medications. Source: Google Images

Why are these treatments helpful for this particular disease?

Buphenyl, Ammonul, Ravicti, and arginine

These drugs function by rapidly decreasing ammonia concentrations. This makes sense as the dysfunctional ASS1 in the urea cycle causes for a build up of ammonia in the system. The drugs are therefore referred to as “pharmacologic nitrogen scavenger therapy,” (Quinonez and Thoene 1993). These scavenger therapies should be given initially as a bolus run over 90 minutes followed by a repeat does run over 24 hours. These therapies function by acting on alternative physiological pathways that stimulate nitrogen excretion in urine (Quinonez and Thoene 1993). As described by Thoene and Quinonez the mechanistic functionality of these therapies are as follows:

Benzoate conjugates with glycine (containing 1 nitrogen) forming hippurate while phenyl conjugates with glutamine (containing 2 nitrogens) forming phenylacetylglutamine with both compounds excreted in the urine. Arginine supplementation in CTLN1 patients repletes the typical deficiency and allows continued excretion of citrulline in the urine.


Diagram explaining the process of dialysis. Source: Google Images
Figure 1: Diagram explaining the process of dialysis.
Source: Google Images


Dialysis is used as an emergency response to elevated plasma ammonia when the nitrogen scavenger therapies fail to do so in time (Quinonez and Thoene 1993). This involves the removal of ammonia by filtering an individual’s blood through a machine (Fig. 1) (“Citrullinemia Type 1 – NORD (National Organization for Rare Disorders)” 2016).

IV Glucose

Intravenous glucose functions to reverse catabolism and promote an anabolic state in the body (Testai and Gorelick 2010).

Strict Diet

Dietary restrictions in patients with CTLN1 usually involve a low protein, high calorie diet with essential amino acids as supplementation. The purpose of this is to limit the amount of protein intake in order to prevent the development of excess ammonia. On the other hand, having just enough protein will ensure proper growth in infant patients (“Citrullinemia Type 1 – NORD (National Organization for Rare Disorders)” 2016).

Monitoring Fluids

Fluid balance must be monitored through patient intake, output and body weight. Patients should remain on the dry side of fluid balance with about 85 mL/kg of body weight per day in infants and appropriate corresponding fluid restriction in children and adults. This is done to maintain control of intracranial pressure (Quinonez and Thoene 1993). Increased intracranial pressure is what contributes to the neurological symptoms of CTLN1 (“Citrullinemia Type 1 – NORD (National Organization for Rare Disorders)” 2016).

Liver transplant

Liver transplants are able to reverse the metabolic abnormality occurring in patients with CTLN1 (Testai and Gorelick 2010). Since the mutations in ASS responsible for ASS1 deficiency in CTLN1 are mostly found in liver cells, it makes sense to replace the entire organ if possible.


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6 Replies to “Treatments and Disease Management”

  1. Hi Stephanie,
    Great job! I thought you did well in explaining the disease thoroughly in an understandable way. On another page, you mentioned that newborns undergo CTLN1 screening, and just by your description alone, it sounds like neonates with the disease have pretty significant symptoms, which I assume would make diagnosis a little easier.

    I can imagine that early diagnosis of late-onset CTLN1 might be difficult for two reasons I can think of – for one, some of the symptoms such as stroke-like episodes, seizures, and liver failure are pretty broad and can come from a lot of different things, and two, since it looks like at least some of the symptoms are caused by ammonia toxicity, which can be caused by just about any Urea Cycle disorder and not just CTLN1. Did you happen to come across any literature about the rate of misdiagnosis? Since plasma quantitative amino acid analysis seems to be a definitive method of diagnosis, do you happen to know how easy, expensive, and frequent this test is performed in patients presenting with symptoms of CTLN1?

    Thank you!

    1. Hi Besher. Thanks for reading and commenting! You make a great point about the early diagnosis of late-onset CTLN1. There are so many Urea Cycle Disorders that present similarly, so it makes sense for there to be some misdiagnosis if not everyone is able to access quantitative amino acid analysis. This method is run in a lab using patient blood samples. This form of analysis used to be very overlooked because of the unreliability of its composition data. However, new instrumentation in the field is augmenting the precision of these tests and so it is getting easier and easier to get better results (Rutherfurd and Dunn 2011). Assuming the patient has sufficient healthcare and insurance as well, this test is pretty easy and inexpensive.

  2. This is excellent, Stephanie!

    In med school we’ve been learning a lot about treating hyperammonemia with lactulose and Rifaximin. Lactulose especially has a fairly safe side effect profile– I was wondering if you came across any studies in the literature looking at either of these medications being used as prophylactic therapies for Type I Citrullinemia?

    Thank you!

    1. Hi Rebecca. Thank you for your kind words. It’s very interesting because I did not come across any of these studies when researching therapies for CTLN1. However, once you told me about lactulose and Rifaximin, I found the studies super quickly! There is a lot of talk about how the medications can help treat hepatic encephalopathy specifically. One study even found that the combination of lactulose and Rifaximin is much more effective than lactulose alone in treating hepatic encephalopathy (Sharma et al. 2013). So cool! Thanks for your comment, because I would have never found this form of treatment for one of the symptoms of this disease.

  3. Great job on your project Steph! You thoroughly covered the disease, and left little room for questions since it was so clear and informative! I’m really impressed! I have just a few questions. Firstly, you mentioned that the disease can present itself as either early-onset or late-onset, and that early-onset occurs during the neonatal period. I’m curious as to how much later CTLN1 can present itself or occur. Is there a reason for why it can stay dormant for a particular amount of time?

    Also, the drug therapies you mentioned deal with the issue of a buildup of ammonia in the body. During your research, did you come across any information as to how the issue of the low concentration of urea cycle products can be treated? Is it really only an issue of a buildup of ammonia, or are there other problems that arise due to the low product concentration?

    1. Thanks a lot Nicole! You’re questions show that you clearly understood the metabolic aspect of this disease which awesome. I’m glad you learned something from reading my posts. One study showed that late-onset CTLN1 can present at 16 months, which is not very late in life but apparently it counts as late-onset since this is not during the neonatal period (Kim et al. 2006). However, other late-onset cases have presented in adult patients (Woo, Park, and Lee 2014). So it seems that there is a large age span where late-onset symptoms can occur. The reason certain patients present at different times in their lives is due to the types of mutations that occur in ASS. Mutations that result in severe deficiency or complete absence of ASS activity lead to the neonatal/early-onset form while mutations that cause partial ASS deficiency will most likely lead to late-onset cases (Ibarra-González et al. 2010). Specifically mutations in highly conservative regions are mainly related to the early-onset neonatal form while homozygous patients with the Gly362Val, Trp179Arg, or Val263Met mutation are associated with a mild/asymptomatic clinical course (Woo, Park, and Lee 2014).

      As for treating the low concentration of urea cycle products such as argininosuccinate in CTLN1 or the high concentration of substrates such as citrulline, the correlation between clinical course and citrulline concentration is poor. Although symptomatic patients usually have very high citrulline concentrations (usually N2000 μmol/L), several patients with high citrulline concentrations but an asymptomatic/ mild course have been reported. In addition, residual enzyme activity is not well correlated with disease course. Although classic neonatal-onset CTLN1 patients show less than 1% of the enzyme activity of healthy individuals, even in patients with undetectable enzyme activity, asymptomatic/mild clinical courses may be present. These findings indicate that biochemical results, except for markedly elevated ammonia concentrations, cannot predict the severity and clinical course of disease (Woo, Park, and Lee 2014). As a result, it seems that the buildup of ammonia is really the main issue with this disease.

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