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