Treatment for OTC deficiency, ASA lyase, CPS1, citrullinemia, urea cycle disorders

OVERVIEW: The treatment of urea cycle disorders consists of dietary management to limit ammonia production in conjunction with medications and/or supplements which provide alternative pathways for the removal of ammonia from the bloodstream. A careful balance of dietary protein, carbohydrates and fats is necessary to ensure that the body receives adequate calories for energy needs, as well as adequate essential amino acids (for cell growth and development). Dietary protein must be carefully monitored and some restriction is necessary; too much dietary protein causes excessive ammonia production. However, if protein intake is too restrictive or insufficient calories are provided, the body will break down lean muscle mass (called catabolism) to obtain the amino acids or energy it requires; this catabolism creates excessive ammonia. Therefore, the correct nutritional balance for each individual in each stage of growth is critical in avoiding hyperammonemic crises. Branched-chain amino acids may be reduced as a result of treatment with ammonia scavenging medication (phenylbutyrate), triggering catabolism; therefore, frequent blood tests (serum ammonia, plasma quantitative amino acids) are required to monitor the disorders and are an important tool for optimizing treatment. 

DIETARY MANAGEMENT: Treatment may include supplementation with special amino acid formulas (Cyclinex, EAA, Trio, UCD I&II), developed specifically for urea cycle disorders, which can be prescribed to provide approximately 50% of the daily dietary protein allowance. Some patients may require individual branched chain amino acid supplementation. Metabolic nutritionists routinely prescribe calorie modules such as Prophree, DuoCal, Benecalorie and ModuCal to be used in combination with the amino acid formulas. Multiple vitamins and calcium supplements are also recommended. New research also suggests that antioxidants may be helpful in minimizing free radical damage to cells in tissue and brain.

DRUG TREATMENT: Two forms of a drug, phenylbutyrate, are FDA approved for treatment of urea cycle disorders, sodium phenylbutyrate (trade name Buphenyl, powder or pill form) and glycerol phenylbutyrate (trade name Ravicti, liquid form). The Foundation played key roles in initiating and supporting the development of these medications. Sodium benzoate is also used in some patients, solely or in combination with phenylbutyrate. All three medications serve as “ammonia scavengers” -- providing alternative pathways for removal of ammonia from the bloodstream and helping to prevent hyperammonemia (elevated blood ammonia).  Carglumic acid (trade name Carbaglu) is approved for treatment of NAGS deficiency. The medications are administered 3-4 times per day as prescribed in order to optimize continual removal of toxic ammonia from the bloodstream. 

Pharmaceutical grade (not over-the-counter) L-citrulline (for OTC and CPS deficiency) or L-arginine free base (ASA and citrullinemia) is also required. These are not to be used in Arginase Deficiency. These supplements help catalyze the urea cycle enzymes and promote optimal removal of ammonia.

H-blockers (antacids) are sometimes prescribed to minimize the gastrointestinal side effects (stomachache, reflux, etc.) of drug treatment.

FEEDING ISSUES: Children with urea cycle disorders often lack appetite (due to excess serotonin in the brain suppressing appetite) and some may benefit from receiving medications and some feedings either via gastrostomy tube (a tube surgically implanted in the stomach) or nasogastric tube (manually inserted through the nose into the stomach).  The access these tubes provide often makes a critical difference in metabolic stability and in averting hyperammonemic crises; medications and formulas can still be administered when children have flu or colds, etc.  Some treatment centers have reported as much as 70% reduction in hospital admissions after placement of G-tubes or parents were trained to use NG-tubes.

MEDICAL TEAMS: Optimal treatment of urea cycle disorders requires a medical team consisting minimally of a geneticist/metabolic specialist, metabolic dietician, nurse practitioner, and developmental specialist or neuropsychologist specifically experienced in successful management of the disorders. These teams are usually found at university hospitals. Specialty consultation and second opinions from experts in the field of UCDs can be obtained by families who live in areas where optimal medical care is not available.

LIVER TRANSPLANT: When optimal treatment fails, or for neonatal onset CPS and OTC deficiency, liver transplant becomes an option.  Liver transplants have been done successfully as a cure for the disorder (although L-arginine supplementation is still necessary in ASA lyase deficiency posttransplant).  The transplant alternative must be carefully considered and evaluated with medical professionals to determine the potential of success and benefits compared to the serious risks and potential for new medical concerns, including the possibility of fatal viruses (Epstein-Barr, CMV), risk of developmental delay or lymphoproliferative disease as a side effect of immunosuppression/immunosuppressants.