N-carbamylglutamate (carglumic acid)

N-carbamylglutamate (NCG, carglumic acid) is widely reported to be the first-line and most effective therapy for NAGS deficiency. Carglumic acid has been shown to improve ureagenesis, growth, biochemical stability, and neurodevelopmental outcomes (F.4633, F.6609, F.7966, F.7166).

Adequate dosing, starting at 100 mg/kg/day, divided into 3-4 doses, rapidly lowers ammonia levels in acute hyperammonemia episodes (F.7166, F.7149, F.6787, F.6902, F.7317, F.4633). Maintenance carglumic acid supports liberalization of protein intake over time, allowing most patients to reach 1.5-2.5 g/kg/day or unrestricted protein intakes, with stable plasma ammonia (F.7166, F.6609, F.7149, F.6787, F.5341). Chronic low-dose carglumic acid (30-100 mg/kg/day) is often effective for long-term management, while higher doses (100-200 mg/kg/day) may be needed during illness (F.7966, F.4923, F.7149, F.6902, F.6787).

Protein Prescription

A protein-restricted diet (commonly 0.5-1 g/kg/day initially) is used acutely to stabilize ammonia levels and prevent catabolism (F.7166, F.6902, F.5341, F.4566, F.6609). However, with carglumic acid therapy, most patients can consume an unrestricted protein diet (F.6609, F.7149, F.6902, F.6787). High-caloric support is also essential to suppress catabolism, particularly during metabolic stress (F.7166, F.7623, F.5341).

Similar to other UCDs (see Recommendation 1), during acute decompensation, protein is temporarily withdrawn or significantly lowered, and intravenous glucose/lipid infusions are used (F.7166, F.7149, F.6609). Case studies note even with carglumic acid supplementation, protocols to reduce protein intake in times of illness may be required, particularly if carglumic acid is not tolerated (F.6609, F.7149).

Delphi 1 Results

Among the seven respondents who reported experience with this disorder, there was high or unanimous agreement on the following statements.

• Individuals with NAGS deficiency who are on an efficacious dose of carglumic acid (i.e., achieved normal ammonia) should follow a diet with unrestricted amounts of protein (i.e., the individual is NOT counseled to track or limit protein intake) and should have a sick day protocol in place for use if/when carglumic acid is not tolerated during illness. (6/7 respondents)
• The sick day protocol should include adequate energy intake (80-120% of usual intake) and reduced protein intake (50% of usual intake). (unanimous agreement)

Delphi 2 Results

Among the eight respondents, there was unanimous agreement that illness/hyperammonemia should be agressively managed with IV glucose/lipids similar to other proximal UCDs when carglumic acid is not tolerated or not available.

Most individuals with NAGS deficiency require initial supplementation with L-arginine or L-citrulline with reported doses ranging from 100-200 mg/kg/day L-arginine (F.7166, F.7149, F.5359) and 150 mg/kg/day L-citrulline (F.5341). Higher doses have also been described; in one report, a child received high-dose L-arginine hydrochloride (700 mg/kg/day) at 13 months of age and was later transitioned to L-citrulline (430 mg/kg/day) following diet liberalization (F.7623). These supplement doses are at times able to be decreased or discontinued with appropriate utilization of carglumic acid; however, plasma concentrations should be followed (F.7166, F.5359).

This topic was not included in the Delphi consensus process.

Monitoring

Ammonia, plasma glutamine, orotic acid, and arginine/citrulline levels should be routinely monitored (F.7166, F.7623, F.5359). Growth, feeding tolerance, and development should be tracked regularly; early and aggressive treatment with carglumic acid improves outcomes (F.7166, F.6609, F.7966). See TABLE #2, Monitoring the Nutritional Management of an Individual with UCD when Well

Nitrogen Scavenger Use

Sodium benzoate or sodium phenylbutyrate (up to 250-500 mg/kg/day) are frequently used for initial hyperammonemia management but is often discontinued once stable on carglumic acid (F.7166, F.7149, F.6787, F.5341, F.6463, F.6902).

L-Carnitine supplementation

Three case reports document the use of L-carnitine supplementation (30-100 mg/kg) (F.4566, F.7345, F.7166) either in response to low plasma concentrations and routine care or as part of the acute decompensation protocol.

Nominal Group

Nominal Group discussion centered on the preference for L-citrulline supplementation over L-arginine. Citrulline does not undergo first pass metabolism in the liver leading to higher availability. Moreover, citrulline can incorporate one nitrogen from aspartate, assisting in decreasing the overall nitrogen pool.

Acute Nutrition Management

Carbonic anhydrase VA (CA-VA) deficiency typically presents with acute metabolic decompensation characterized by hyperammonemia, hypoglycemia, metabolic acidosis, and elevated lactate (F.5060, F.5979, F.6788, F.7102, F.5284). Similar to other UCDs, management centers on rapid correction of hyperammonemia and suppression of catabolism, see Recommendation 1. Case reports and small case series consistently describe temporary protein withdrawal or restriction and provision of non-protein calories with IV dextrose (e.g., 6-10 mg/kg/min) and ILE to suppress catabolism (F.6788, F.5979, F.5284). Nitrogen scavengers are commonly administered (F.5788, F.7102), and carglumic acid (50 mg/kg/day) is frequently used to stimulate CPS1 activity and enhance urea cycle function, although it is not formally approved for CA-VA deficiency (F.5060, F.5979, F.6788, F.5284). Hemodiafiltration and peritoneal dialysis have also been used to rapidly lower ammonia concentrations in severe cases (F.6788, F.7102). Following the initial metabolic crisis, some individuals are discharged on a low- or protein-controlled diet (F.5979, F.6788, F.7102).

Long-Term Management and Monitoring

Clinical course varies after the initial crisis. While many individuals experience a single metabolic crisis followed by stability, others may have a second crisis or recurrent decompensation, neurologic sequelae, or early mortality despite metabolic correction (F.6788, F.5060, F.7102, F.5284, F.5797). These outcomes highlight the importance of early diagnosis, aggressive acute management, and continued neurologic and metabolic monitoring.

Some individuals benefit from ongoing management strategies, including a protein-controlled diet (approximately 1-2.5 g/kg/day) and continued use of nitrogen scavengers (F.7102). During intercurrent illness, sick-day protocols may include temporary protein reduction, continued administration of carglumic acid, and provision of adequate non-protein energy to prevent catabolism (F.5979, F.6788), see also Recommendation 1.7.

Delphi 1 Results

Among the five respondents who reported experience with this disorder, 4/5 respondents agreed that when well, most individuals with CA-VA deficiency do not require a low protein diet to prevent hyperammonemia.

There was unanimous consensus that a sick day protocol should be in place for use during illnesses. The sick day protocol should include adequate energy, and reduced protein intake (50% usual intake), and respondents agreed it should also include carglumic acid.

Delphi 2 Results

Among three respondents, two somewhat agreed and one somewhat disagreed that carglumic acid (50 mg/kg/d) should be considered to support metabolic stability.

Monitoring

In addition to standard UCD biochemical monitoring (See TABLE #2, Monitoring the Nutritional Management of an Individual with UCD when Well ), consider monitoring lactate as an early marker of metabolic decompensation. Elevated blood lactate is a common and consistent finding in CA-VA deficiency and is reported across nearly all case series and reports. In one multicenter review, elevated lactate was noted as part of the distinct biochemical fingerprint of CA-VA, alongside hyperammonemia and ketonuria (F.5060). In a 4-patient case series, all had elevated lactate at presentation, supporting the secondary CPS1 deficiency hypothesis as a contributor to hyperammonemia (F.5979). Case reports in neonates highlighted lactate elevation as an early marker during initial metabolic crises (F.6788, F.7102). In some patients, lactate normalized after metabolic stabilization, although severe cases may show continued clinical decline despite improvement in lactate and ammonia concentrations (F.5284).

Additional Supplements Utilized

In a single case report, mitochondrial-targeted supplementation (e.g., L-carnitine and multivitamin complexes such as Cytoflavin, containing succinic acid, nicotinamide, inosine, and riboflavin) was utilized and shown to have some benefit during initial presentation (F.7757).

These topics were not included in the Delphi consensus process.

Lactose/Galactose Restriction and Medium Chain Triglycerides (MCT)

In infants, lactose or galactose restriction is essential because lactose exacerbates cholestasis symptoms. Resolution of jaundice and normalization of biochemical markers have been observed when infants are provided galactose-free or lactose-free formulas (F.4988, F.5106, F.5496, F.7210). Additionally, MCTs are frequently incorporated into the diet, as they bypass the cytosolic NADH pathway, providing an efficient energy source directly metabolized by hepatocytes. Several infant case reports described clinical improvement following the use of lactose-free, MCT-enriched infant formulas, which typically provide 30-50% of total fat as MCT (F.4988, F.5255, F.5257, F.5496, F.5731, F.7210), or "MCT milk" (F.6363).

Macronutrient Distribution

Unlike standard UCDs, a primary nutrition intervention in NICCD is the avoidance of carbohydrate-rich diets. High carbohydrate intake exacerbates cytosolic NADH accumulation within hepatocytes, deteriorating the metabolic state. Specific macronutrient distributions have been documented in several reports. One infant demonstrated normalization of growth and laboratory parameters on a diet composed of 20% protein, 45% fat, and 35% carbohydrate, supplemented with MCTs (F.7885). In another case, provision of a high-protein (3 g/kg/day), galactose-free diet resulted in normalization of biochemical and clinical parameters over 14 months of follow-up (F.5106).

Supplements

To further support liver function, especially in cholestatic presentations, supplementation with fat-soluble vitamins (A, D, E, and K) and ursodeoxycholic acid (UDCA) has been utilized effectively in multiple case reports (F.5106, F.7210, F.5496, F.5731, F.5255, F.5257, F.7344, F.7210, F.7334). In a survey of pediatricians reporting on 75 individuals with genetically confirmed NICCD, 51 were treated with fat-soluble vitamins and 31 were treated with UDCA (F.6772). Dosing reported for fat soluble vitamins in one 2.5-month-old male was 400 IU/kg/d vitamin A, 400 IU/day vitamin D, 5 mg/kg/day vitamin E (F.7210). Doses for UDCA ranged from 10-20 mg/kg/day (F.7210, F.7334).

Duration of Nutrition Treatment

There is variability in practice about the duration of dietary treatment in infants with NICCD. One case report demonstrated that cholestasis and related biochemical abnormalities resolved spontaneously between 6 and 12 months of age (F.5694). Some infants successfully transitioned back to unrestricted diets without recurrence of significant clinical symptoms after initial nutrition management led to biochemical normalization (F.6363, F.5106). Thus, some clinicians consider discontinuing diet restrictions once biochemical parameters normalize and clinical symptoms resolve.

In contrast, other reports urge caution. While biochemical normalization is often achieved, longer-term observations suggest that some patients may develop subtle biochemical, clinical, or behavioral abnormalities later in childhood, including during periods traditionally assumed to be "silent" or clinically healthy (F.4988, F.7210). Several authors also caution against premature discontinuation of nutrition management, noting that this may increase vulnerability to clinical deterioration under metabolic stress or illness (F.5731).

Delphi 1 Results

Among seven respondents who reported experience with NICCD, they reached consensus on the following treatment practices:

• Implement galactose restriction for individuals with hypergalactosemia (7/7 respondents) .
• Use of MCT supplementation via MCT-containing infant formula or MCT oil (6/7 respondents with one neither agreeing nor disagreeing).

The following practices did not reach consensus:

• Use of fat-soluble vitamin supplementation (5/7 respondents).
• Use of a "high protein diet", which was defined as >10% of total energy from protein or 2.5-3.5 g protein/kg/d (5/7 respondents).
• Discontinuation of dietary galactose restrictions (4/7 respondents) and MCT supplementation (4/7 respondents) after the first year and following normalizations of liver function tests and correction of cholestasis.
• Use of phenylalanine- and tyrosine-free medical foods was not supported (1/7 respondents).

Delphi 2 Results

There was no consensus for the following treatment practices among 11 respondent:

• Supplement with fat-soluble vitamins to support liver health (8/11 respondents). Two respondents neither agreed nor disagreed and one respondent disagreed.
• Consider providing ursodeoxycholic acid in infants experiencing cholestasis to support liver health (5/11 responents).
• Consider discontinuing galactose restrictions after 12 months of age and normalization of liver function tests, while ensuring regular clinical and biochemical monitoring continues (8/11 respondents). Two respondents disagreed and one respondent neither agreed nor disagreed.

Nominal Group

Nominal group participants noted that galactose or lactose restriction may be discontinued after one year of age if liver findings and jaundice have resolved.

Macronutrient Distribution

Many individuals with citrin deficiency exhibit a preference for high-protein and high-fat foods, likely reflecting metabolic self-regulation. Dietary treatments commonly adopt these preferences by emphasizing increased protein and fat intake while limiting carbohydrates, leading to improved clinical outcomes (F.7894, F.6516, F.6323). Specific macronutrient distributions have been documented in several publications. In a case series of three adults with CTLN2, diets averaging 21.5% protein, 39.9% fat, and 37.1% carbohydrate, supplemented with oral sodium pyruvate, were associated with sustained biochemical improvement over three years (F.7894). Another case series described varied but similar macronutrient distributions ranging from 15-20% protein, 34-50% fat, 35-54% carbohydrate, with MCT oil providing 0.8% of energy for some cases, which led to biochemical and symptomatic relief (F.6516).

As in NICCD, MCTs may be beneficial, as they bypass the cytosolic NADH pathway and provide an efficient energy source directly metabolized by hepatocytes. In one larger cohort describing 43 individuals with CTLN2, 13 were treated with MCT oil with a typical dose of 8-10 mL/day (F.6781). Another case series of two individuals provided MCT doses of 5-30 mL/day with a macronutrient distribution of 14-22% protein, 24-50% fat, and 35-54% carbohydrate (F.5956).

In contrast, carbohydrate intake exceeding 60% of total energy has been associated with clinical deterioration, including an increased frequency of hyperammonemic encephalopathy (F.5533, F.4978). High carbohydrate intake promotes cytosolic NADH accumulation within hepatocytes, which may further impair metabolic stability. Multiple reports describe worsening hyperammonemia and encephalopathy following carbohydrate administration, including during hospitalizations (F.6660, F.4978, F.5533).

Notably, protein-restricted diets commonly prescribed for UCDs (e.g., ≤1 g/kg/day) have been associated with clinical deterioration in at least one adult case, which was attributed to compensatory increases in carbohydrate intake (F.4978). In contrast, another adult with protein intake consistent with the DRI (50-70 g/day) demonstrated gradual clinical improvement (F.4978).

Delphi 1 Results

Thirteen clinicians responded to questions regarding CTLN2. There was agreement among 11/13 respondents with the following treatment practices. For both, two respondents neither agreed nor disagreed.

• Provide a diet with the following protein, fat, carbohydrate (PFC) ratio (as a percentage of total energy intake): Protein: 15-30%; Fat: 40-50%; Carbohydrate: 30-40%.
• Use of MCT supplementation.

Certain therapies are contraindicated. Intravenous dextrose infusions have resulted in rapid clinical deterioration in adult-onset CTLN2 cases, underscoring the detrimental impact of excessive carbohydrate exposure (F.6660). Similarly, standard hepatic encephalopathy diets featuring low protein and high carbohydrate content (e.g., 10% protein, 75% carbohydrate) have worsened patient outcomes by exacerbating hyperammonemia and neuropsychiatric symptoms (F.4978, F.5533). In addition, misdiagnosis of citrin deficiency as a typical UCD or other metabolic disorder, leading to inappropriate dietary management with protein restriction and glucose infusions, has also resulted in delayed diagnosis and significant clinical deterioration (F.4597, F.7882, F.5682).

This topic was not included in the Delphi consensus process.

Supplementation

Pharmacological supplementation also plays a role in management. Sodium pyruvate, used orally at dosages of 100-300 mg/kg/day in three adults, supported mitochondrial energy metabolism and aided in ammonia detoxification (F.7894). L-arginine supplementation, dosed from 3 g/day up to 18 g/day, has also demonstrated efficacy in improving ammonia metabolism and reducing neurological symptoms in several adult cases (F.7210, F.6323). L-carnitine supplementation is beneficial in infants presenting with concurrent carnitine deficiency (F.5685).

There are insufficient data to support routine use of sodium pyruvate or L-arginine supplementation in citrin deficiency; therefore, no recommendation is made at this time.

Liver Transplantion

Liver transplantation has resulted in normalization of biochemical profiles, permanent resolution of symptoms, and complete removal of dietary restrictions, allowing individuals to consume an unrestricted diet without recurrence of disease manifestations (F.7894, F.7318, F.7220, F.7029).

Delphi 1 Results

There was no agreement among 13 respondents reporting experience with CTLN2 regarding sodium pyruvate (5/13 respondents) or L-arginine supplementation (7/13 respondents) in individuals with CTLN2, with most respondents neither agreeing nor disagreeing with their use.

A protein-restricted diet in HHH syndrome has been associated with improvements in plasma ammonia concentrations, liver function tests (LFTs), and cognitive outcomes across multiple case reports and series (F.4905, F.4968, F.5037, F.6583, F.6978, F.7060, F.7953). In addition to biochemical improvements, reduced protein intake was associated with improvements in neurological symptoms such as ataxia, spasticity, and seizures (F.6649).

In children, reported protein intakes ranged from approximately 0.9 g/kg/day (F.7953, F.6978) to 1-1.8 g/kg/day during childhood (F.5037), with one single case report describing intakes of 1.5-1.7 g/kg/day in children aged 1-2 years (F.4905). In adolescents and adults, a case series reported protein intakes of approximately 40 g/day (F.5037), while a single adult case described a protein intake of 0.5 g/kg/day (F.7060). Similar to other UCDs, protein aversion and spontaneous self-restriction were commonly observed, particularly prior to diagnosis (F.5037, F.7953, F.6795). Overall, reported pediatric protein tolerance in HHH syndrome ranged from 0.9 to 1.8 g/kg/day, with prescriptions individualized based on clinical response. Evidence describing protein tolerance in adults is limited.

Delphi 1 Results

Among the 12 respondents who reported experience with HHH syndrome, 10/12 respondents agreed that nutritional and/or pharmacological management did not differ from other UCDs. Noted differences included experience with a mild subset of patient who only require monitoring yearly and may or may not require L-citrulline.

Delphi 2 Results

Among seven respondents, 6/7 respondents agreed with the statement proposing prescription of the highest protein intake an individual can tolerate, including typical protein goals of 1.0-1.8 g/kg/day in childhood and approximately 0.8-1.0 g/kg/day in adulthood.

Case reports in individuals with HHH syndrome suggest that L-arginine supplementation aimed at supporting urea cycle function may improve neurological outcomes, including seizure control and encephalopathy management (F.7320, F.7331). In contrast, one case report discussed the possibility that higher doses of L-arginine may have contributed to seizure activity (F.7320).

The 2019 European UCD guideline addressing HHH syndrome recommended L-citrulline as a preferred supplement, with suggested doses of 100-250 mg/kg/day, and identified L-arginine as an alternative option (100-200 mg/kg/day in individuals <20 kg or 2.5-6 g/m²/day in those >20 kg) (F.7963).

Delphi 2 Results

Among seven respondents who reported experience with HHH syndrome, there was agreement with L-citrulline supplementation (100-250 mg/kg/day) to replenish plasma levels and support metabolic stability (6/7 respondents).

Nominal Group

Nominal group experts agreed or strongly agreed that L-citrulline supplementation should be preferred over L-arginine.

Monitoring

A retrospective review of 16 individuals and a case series of four individuals with HHH syndrome described cognitive and psychomotor delay despite normal and near normal ammonia concentrations (F.5037, F.7160). This suggests that hyperornithinemia itself may contribute to neurotoxicity, independent of ammonia. This cohort further noted the use of urinary orotic acid to monitor the effect of protein restriction and made changes in prescription based on results (F.5037). Neurodevelopmental evaluations to track progression and guide therapy are recommended, as is MRI imaging in cases with cognitive decline or seizures to monitor leukoencephalopathy (F.7331, F.7160). See TABLE #2, Monitoring the Nutritional Management of an Individual with UCD when Well for additional monitoring recommendations.

Nitrogen scavengers

Nitrogen scavengers, such as sodium benzoate given at doses of approximately 290 mg/kg/day, are associated with biochemical improvement when combined with protein restriction (F.7953, F.5037, F.6978). See also Recommendation 4.1

Additional Supplements

One case report (F.4883) suggests ornithine supplementation of 1 mmol/kg/day was instrumental in improving protein tolerance up to 1.2-2.0 g/kg/day. A case series of four patients with HHH Syndrome were all given lysine supplementation (dose not specified) and authors suggest this may have a role in patients with impaired intracellular ornithine transport, though evidence is limited (F.7160). The 2019 UCD guidelines suggest creatine may be considered for patients with documented low plasma creatine (F.7963). Finally, authors from one case report propose using antioxidants in the context of suspected mitochondrial dysfunction, though further research is needed (F.6795).

Treatment and Monitoring During Pregnancy

One case report described a woman with HHH syndrome who experienced recurrent complications across three pregnancies (F.7160). She was maintained on a moderately protein-restricted diet, with 40 g/day prescribed during her first pregnancy after mild hyperammonemia was detected at 11-12 weeks' gestation (adherence unclear). She developed seizures during two of the three pregnancies. Following her first and second Cesarean deliveries, she experienced postpartum hyperammonemia, which responded to treatment with nitrogen-scavenging therapy and intravenous L-arginine. One infant had intrauterine growth restriction, and another was born with transient respiratory distress.

This topic was not included in the Delphi consensus process.

Protein prescriptions are individualized to minimize nitrogen load while supporting growth and metabolic stability. In children, commonly reported targets range from 1.0-1.5 g/kg/day (F.5420, F.5765, F.6139, F.6860, F.7505), while adult intakes of 0.8-1.0 g/kg/day and up to 1.2 g/kg/day have been described (F.6193, F.7582). Higher protein intakes may be tolerated in selected cases. For example, in a 2-year intervention study including individuals aged 2 to 33 years, protein intake was increased from 0.5-1.5 g/kg/day to 1.0-2.0 g/kg/day following initiation of L-citrulline supplementation (F.7504). Despite this increase, some clinical manifestations, including hepatosplenomegaly and osteoporosis, persisted (F.7504). In another report, an 8-month-old male tolerated protein intakes up to 2.6 g/kg/day (F.6848). Overall, the available data support moderate protein restriction in LPI, with typical pediatric targets of 1.0-1.5 g/kg/day and adult targets of 0.8-1.0 g/kg/day, individualized based on clinical status, growth, and tolerance.

Protein restriction is essential in managing LPI. However, excessive restriction, particularly during periods of growth, can contribute to malnutrition, growth failure, and bone disease. Failure to thrive, short stature, and low BMI are commonly reported, often reflecting poor protein intake, aversion to protein-rich foods, and underlying metabolic disturbances (F.6074, F.6713). Several studies report a high prevalence of osteopenia and osteoporosis in LPI, with low protein intake associated with impaired bone formation and defective collagen synthesis due to amino acid deficiencies (F.6863, F.7582). However, not all growth failure is diet-related. A 2006 case report described persistent growth failure in a child despite good dietary compliance, suggesting non-dietary factors such as growth hormone deficiency may also contribute (F.5420). Even in cases where L-citrulline supplementation improves protein tolerance, increasing protein intake may not fully reverse bone deficits once established (F.7504).

Delphi 2 Results

Among thirteen respondents reporting experience with LPI, there was unanimous agreement that clinicians should prescribe the highest protein goal an individual can tolerate, typically 1-1.5 g/kg in infants and children and 0.8-1 g/kg in adults.

L-Citrulline Supplementation

L-citrulline supplementation is widely used in the management of LPI to improve nitrogen metabolism and increase protein tolerance. Mechanistically, L-citrulline is preferred over L-arginine because it bypasses the defective intestinal transport of dibasic amino acids in LPI, is better absorbed, and is converted in the liver and kidneys into arginine and ornithine. L-citrulline supplementation has also shown greater efficacy and fewer gastrointestinal side effects compared to L-arginine (F.6366, F.7504). Doses reported in the literature range broadly from 73-500 mg/kg/day (F.6192, F.6860, F.6864), with common targets between 100-170 mg/kg/day, (F.5420, F.5765, F.6074, F.7093) typically divided into multiple daily doses (F.7728, F.7949). Monitoring treatment adequacy may include plasma amino acids and urinary orotic acid, which typically decreases with effective supplementation (F.5339, F.7504).

Positive clinical outcomes associated with L-citrulline therapy include improved protein tolerance, growth, metabolic control, and reduced gastrointestinal and neurological symptoms (F.5339, F.5765 F.6366). For example, a 4-year-old female treated with up to 5.7 g/day experienced improved growth, improved protein tolerance (~2 g/kg/day), normalized liver size, and enhanced bone density (F.5339). In a 1989 case, two adult brothers showed clinical and biochemical improvements including weight gain and resolution of neurological symptoms when treated with 3-4 g L-citrulline/day (F.7767). A 2-year intervention study with 19 individuals receiving 2-3.5 g L-citrulline/day reported diminished protein aversion in most, improved physical performance, and catch-up growth in 7 of 9 stunted children (F.7504). In another case, 3 g L-citrulline divided three times daily reduced plasma ammonia and increased urinary nitrogen excretion in a 35-year-old woman (F.6796). The lowest effective doses appear to start around 100 mg/kg/day, as supported by a case of a 12-month-old whose gastrointestinal symptoms resolved on 100 mg/kg L-citrulline (F.5765). In contrast, high doses up to 500 mg/kg/day have also been reported (F.6860, F.6864). However, L-citrulline supplementation does not correct all complications of LPI, as hepato- and splenomegaly, osteoporosis, and immunologic abnormalities may persist despite adequate therapy (F.7504, F.6366).

L-Arginine Supplementation

L-arginine supplementation has historically been used in the management of LPI to support urea cycle function and correct secondary arginine deficiency, though its use has largely declined in favor of L-citrulline due to better efficacy and tolerability (F.4876, F.7501, F.7507). Studies report modest improvements in plasma amino acid profiles and linear growth in children (F.4876), as well as improved ammonia clearance and nitrogen excretion in adults (F.6796). One case also demonstrated improved vascular and coagulation parameters with high-dose intravenous L-arginine (F.7216). However, L-arginine is poorly absorbed in the intestine in LPI and is frequently associated with gastrointestinal side effects, such as diarrhea, especially at higher doses (F.7504). Comparative studies have shown that L-citrulline is more effective than L-arginine at raising plasma arginine and ornithine concentrations with fewer adverse effects (F.7501, F.7507).

Delphi 2 Results

Among thirteen respondents who reported experience with LPI, there was strong agreement (12/13 respondents) with the use of L-citrulline supplementation, in divided doses providing a total of 100-170 mg/kg/day.

Several studies have used plasma amino acid profiles to evaluate the metabolic status of individuals with LPI. Common findings include persistently low plasma concentrations of cationic amino acids—especially lysine, arginine, and ornithine—even with L-citrulline or L-lysine supplementation (F.5742, F.6194, F.6956). In multiple studies, urinary excretion of lysine, arginine, ornithine, citrulline, and glycine remained elevated despite treatment, reflecting the underlying transport defect (F.5742, F.6189, F.7507).

Renal function is often monitored using serum creatinine and cystatin C (F.6191, F.6193). Cystatin C has been increasingly used as a marker of renal function in individuals with LPI, given its relative independence from factors such as muscle mass, age, and sex (F.6190). In a retrospective Finnish cohort, 59% of individuals had elevated cystatin C, and 38% had elevated creatinine, with end-stage renal disease documented in 10% of the cohort (F.6190). Studies have shown that cystatin C correlates with urinary lysine concentrations and may detect renal dysfunction earlier than creatinine (F.6899). Other markers include serum creatinine, urine protein, and urinary β2-microglobulin, all of which can help assess glomerular and tubular function (F.6190, F.6899).

Ferritin is frequently elevated in individuals with LPI (F.6848, F.6860, F.6864, F.5147, F.5171, F.6713), but its interpretation is complex. Studies have shown that high ferritin concentrations often occur despite normal serum iron and transferrin saturation, suggesting that elevations reflect metabolic stress or inflammation rather than iron overload or sufficiency (F.7500). As such, ferritin should not be used in isolation to assess iron status in LPI. Instead, it may serve as a nonspecific marker of disease activity, and should be interpreted alongside other iron parameters and clinical context.

Low intakes of nutrients relevant to bone health, including calcium, vitamin D, iron, and zinc have been reported (F.6192). Periodic DXA scans are also used to monitor bone health, particularly those with growth delays, history of fractures, or poor protein tolerance (F.6863, F.6864, F.4942).

Delphi 1 Results

Among the nine respondents, there was no consensus on the appropriate monitoring frequency for cystatin C or ferritin in clinically stable individuals with LPI.

• For cystatin C, 6/9 respondents recommended annual monitoring, while 2/9 preferred monitoring at every clinic visit.
• For ferritin, 5/9 respondents favored monitoring at every clinic visit, and 3/9 preferred annual assessment.

Delphi 2 Results

Among 13 respondents, there was agreement (11/13 respondents) to monitor cystatin C and other markers of kidney disease at least annually.

L-Lysine Supplementation

L-lysine supplementation in LPI is considered as a supportive therapy in individuals with documented lysine deficiency or related symptoms such as poor growth, hypotonia, and hair or skin changes. While lysine is one of the dibasic amino acids poorly transported in LPI, some studies suggest that small, individually titrated doses of L-lysine may improve plasma concentrations and potentially alleviate symptoms without causing metabolic decompensation.

A 2007 study in 27 Finnish individuals reported using L-lysine hydrochloride at individualized doses ranging from 8 to 46 mg/kg/day (mean 22.7 mg/kg/day), divided 3-4 times daily with meals, over a mean of 30 months (F.6194). Plasma lysine concentrations increased from below to within the normal range in most patients without adverse effects (F.6194). This suggested that carefully titrated L-lysine supplementation was well tolerated and could correct plasma lysine concentrations, although its efficacy in resolving clinical symptoms remains to be determined. In a 2000 Turkish study, intravenous L-lysine infusion produced a transient rise in plasma lysine without inducing hyperammonemia or other metabolic disturbances (F.5743). Similarly, a Finnish 2003 study found that oral L-lysine, when given with L-citrulline and a protein-restricted diet, did not impair urea cycle function or elevate ammonia (F.5742). However, higher L-lysine doses (1.1 mmol/kg) triggered gastrointestinal side effects like diarrhea in some adults, emphasizing the need for individualized dosing. A narrative review (F.7728) and a Finnish cohort (F.6193) also supported oral L-lysine in doses ranging from 10-40 mg/kg/day to correct plasma deficiencies. In a 2011 case report of a 5-year-old boy, L-lysine at 27 mg/kg/day (divided into 3 doses) modestly improved plasma amino acid profiles but had limited impact on clinical growth over a one-year period (F.7949).

L-Carnitine Supplementation

Evidence from case reports and observational studies supports the efficacy of L-carnitine supplementation in normalizing plasma carnitine concentrations and improving clinical outcomes. A 1987 case report demonstrated that oral L-carnitine (400-600 mg/day) significantly increased plasma and urinary carnitine lconcentrations in an 11-year-old boy with LPI and hypocarnitinemia, and unexpectedly, also raised plasma lysine (F.6224). In a 2002 case report, a child receiving L-citrulline and L-carnitine (50 mg/kg/day) experienced improved well-being, appetite, and activity levels after one month of therapy, along with normalization of carnitine concentrations (F.7093). Similarly, a 2016 case report described clinical improvements in behavior and spleen size in a child with LPI following a treatment regimen that included L-carnitine at 100 mg/kg/day (F.4724). A study from Finland screened 37 females with LPI (ages 8–52) for carnitine deficiency; 8 received L-carnitine supplementation at a fixed dose of 1 g/day (F.6191). All individuals demonstrated increased serum carnitine concentrations, and most experienced resolution of muscle weakness. This study emphasized the importance of monitoring total and free carnitine concentrations, as well as their ratio, to identify candidates for supplementation (F.6191). A 2011 narrative review also supports this clinical approach, recommending L-carnitine at 25–50 mg/kg/day in LPI patients with confirmed carnitine deficiency (F.7728).

Other Considerations

Osteopenia and osteoporosis are frequent complications, especially in younger individuals, with evidence of reduced bone mineral density and impaired collagen synthesis attributed to chronic protein deficiency and cationic amino acid depletion (F.6863, F.4942). Renal involvement is also common and can include tubulopathy, proteinuria, hematuria, and progression to chronic kidney disease or end-stage renal disease in some individuals (F.6190, F.6191, F.6956, F.6074). Pulmonary complications, including interstitial lung disease and alveolar proteinosis, have been reported in both children and adults (F.6864). Hematologic abnormalities such as anemia, leukopenia, and thrombocytopenia are frequently observed and may be exacerbated during stress or illness (F.7093, F.7505, F.5562). Additionally, individuals may exhibit hepatosplenomegaly, hyperlipidemia, and signs of immune dysfunction or autoimmunity, including episodes of hemophagocytic lymphohistiocytosis (HLH) and positive autoimmune serologies (F.6074, F.5219, F.5171).

Delphi 1 Results

Among nine respondents who reported experience with LPI, there was agreement (8/9 respondents) to consider starting L-lysine supplementation (10-40 mg/kg/day) in individuals with ≥2 consecutive low plasma lysine concentrations who are currently on a low protein diet with L-citrulline supplementation.

There was unanimous agreement to consider supplementing with L-carnitine (25-50 mg/kg/day) if free/total carnitine is low.

Five publications addressed pregnancy in individuals with LPI, including four case reports (F.4935, F.5562, F.6156, F.6805) and one case series of 18 pregnancies in nine Finnish mothers (F.6189). A 1995 case report described a Japanese woman with LPI who maintained metabolic stability during pregnancy using L-citrulline and lactulose (F.5562). Although she experienced anemia and thrombocytopenia, there were no severe maternal complications or hyperammonemic episodes, and the pregnancy concluded with the vaginal delivery of a healthy infant. In a 2013 case series from Turkey, one of six individuals became pregnant and experienced no complications other than moderate anemia (hemoglobin 7.3 mg/dL) (F.4935). She followed a protein-restricted diet (1 g/kg/day) with L-citrulline (5 g/day) and delivered a healthy infant. A 2006 Japanese case report described a woman with LPI who maintained metabolic control during pregnancy with a low-protein diet (0.7 g/kg/day) and L-citrulline/L-ornithine supplementation (200 mg/kg/day); despite anemia requiring transfusion, ammonia concentrations remained stable, and she delivered a healthy infant via cesarean section (F.6805). A 2013 case reported a woman with LPI managed with a low-protein diet (1 g/kg/day), vitamin B12, and L-arginine, along with red blood cell transfusion and prednisone for thrombocytopenia (F.6156). She delivered a healthy infant via cesarean at 37 weeks, which was followed by "intensive metabolic monitoring" in the early postpartum period and stepwise protein advancement from 0.5 to 0.8 g/kg/day before discharge on postoperative day 9 (F.6156).

A 2006 Finnish retrospective review of 18 pregnancies in nine women with LPI found a high rate of toxemia (44%), with one case progressing to hypertensive crisis (F.6189). Plasma amino acid analysis revealed consistently low concentrations of lysine and ornithine, along with elevated urinary excretion of several amino acids. Some individuals also showed signs of essential amino acid deficiency, including persistently low plasma leucine and isoleucine, and 21% of infants were small for gestational age. Anemia was frequent, often requiring transfusion despite appropriate iron supplementation. The authors proposed a structured monitoring protocol consisting of monthly assessment of blood pressure, urinary protein, and urinary orotic acid; bimonthly hematologic monitoring; and every four months broader evaluation of nutritional markers (e.g., plasma and urinary amino acids, albumin, prealbumin, retinol-binding protein, zinc, calcium, magnesium, copper), renal function (including 24-hour urinary protein and creatinine clearance), thyroid studies, liver-related markers, and inflammatory markers (F.6189).

This topic was not included in the Delphi consensus process.

Protein Prescription

A protein-restricted diet with EAA-based medical food to decrease arginine intake is widely used to reduce plasma ornithine. Reported dietary regimens typically limit total protein to 0.5-1.0 g/kg/day, often combined with EAA-based medical foods at doses ranging from 0.2-0.5 g/kg/day to ensure nutritional adequacy (F.5293, F.6334, F.6149, F.6521, F.7452, F.7458, F.7615, F.7889). Two case reports provide specific arginine intake goals targeting a range of 12-18 mg/kg/day (F.6470, F.6096). Other reports have implemented a fixed arginine intake of 125-250 mg/day during the initial phase of dietary intervention, with some individuals gradually increasing up to 1500 mg/day as tolerated (F.4649, F.6095). These interventions commonly resulted in plasma ornithine reductions of 40-75% (F.4600, F.5136, F.5293, F.6334, F.5890, F.6149, F.6096, F.7458, F.7198), with some reporting even greater reductions (F.7456). In cases of severe restriction, ornitine concentrations were reduced to near-normal within weeks, though symptoms of hyperammonemia occasionally occurred if arginine was excessively restricted (F.6470, F.6095, F.6096). Some case reports describing severe protein restriction indicated that adherence to these prescribed goals was challenging for patients (F.5293, F.6334).

Improvements in visual outcomes remain inconsistent. While most case reports noted stabilization or modest improvements in visual fields, color vision, or dark adaptation (F.7456, F.6096, F.7237, F.7452, F.7944, F.6335, F.6521, F.7615, F.7454, F.7161, F.6096), others reported continued progression of chorioretinal atrophy despite effective biochemical response (F.4708, F.6470, F.7880). A large longitudinal study of 27 individuals showed that those who adhered to an arginine-restricted diet had slower progression of retinal dysfunction measured by electroretinogram (ERG) and perimetry compared to non-adherent individuals (F.7454). However, not all studies were able to confirm a clear link between plasma ornithine reduction and visual stabilization, especially when treatment was initiated later in life (F.4708, F.6470, F.7615).

Pyridoxine (Vitamin B6) Supplementation

A small subset of individuals (estimated <10%) are responsive to high-dose pyridoxine, with plasma ornithine reductions of 25-50% and potential stabilization of vision (F.5512, F.6040, F.6765, F.7459). Typical doses range from 100-600 mg/day with 300 mg/day commonly reported (F.4709, F.7161, F.6765, F.5512, F.6517, F.7459, F.6518, F.5553). Both low (15-18 mg/day) and high doses (600-700 mg/day) have been effective in responders (F.7198). However, most are non-responders to pyridoxine and do not benefit from this therapy alone (F.5951, F.7198, F.7535).

Creatine Supplementation

Creatine supplementation in OAT has been evaluated in several observational studies, case series, and one long-term follow-up study. Its use is based on the observation that elevated plasma ornithine inhibits creatine biosynthesis, leading to secondary creatine deficiency in muscle and brain tissues. Supplementation aims to restore intracellular creatine levels and improve energy metabolism, particularly in muscle, though its effect on visual outcomes is limited. Typical regimens include oral creatine monohydrate at 1.5-2.0 g/day in divided doses (F.7311, F.6678, F.7806, F.5975), with lower doses (e.g., 0.25 g three times daily) used in younger children (F.5975). In some studies, creatine precursors such as guanidinoacetate (330-880 mg/day) and L-methionine (420-1120 mg/day) were used as alternatives (F.7311, F.6678).

Several studies demonstrate improvement in skeletal muscle histology with creatine supplementation. In a long-term study of 13 individuals with OAT (aged 6-31 years), muscle biopsy abnormalities (atrophic patches and tubular aggregates) resolved in all of those treated with 0.5-1.5 g/day creatine, while muscle atrophy returned in those who discontinued supplementation (F.5975). Similarly, in a one-year study of seven individuals, type II muscle fiber diameter increased significantly, and the percentage of affected fibers decreased, especially in adults (F.7806). Studies using phosphorus magnetic resonance spectroscopy (31P-MRS) found that creatine supplementation normalized the phosphocreatine/inorganic phosphate (PCr/Pi) and PCr/ATP ratios in muscle, approaching concentrations in healthy controls (F.7311, F.6678).

In contrast, creatine supplementation does not appear to improve visual acuity or halt retinal degeneration. Despite reported muscle improvements, creatine supplementation has not consistently improved visual outcomes. In the 13-patient study, visual acuity declined in most eyes, visual fields constricted in the majority, and ERG responses were reduced or absent throughout follow-up (F.5975). Another study found visual field progression in younger individuals, while older individuals showed more stability (F.7806). These findings suggest that creatine may not adequately reach retinal tissues or that other mechanisms contribute to disease progression in the eye (F.7311, F.7806). Evidence of brain creatine deficiency has also been reported on MRS, particularly in individuals with high plasma ornithine (F.6477), though the effects of creatine supplementation on brain creatine concentrations and neurological outcomes remain unclear, and higher dosing may be required (F.6477, F.6678).

Monitoring

Several studies note that maintaining plasma ornithine concentrations below 500 µmol/L may be associated with stabilization of retinal changes (F.6096, F.7452, F.7454, F.7161), though the exact threshold for disease progression prevention is unclear. Serial monitoring of plasma ornithine, lysine, and ammonia, as well as ophthalmologic evaluations (e.g., visual acuity, ERG, fundus exams), is recommended, though monitoring frequency is rarely specified in the literature. See TABLE #2, Monitoring the Nutritional Management of an Individual with UCD when Well for monitoring recommendations for typical UCDs.

Delphi 1 Survey

Among the10 respondents who reported experience with OAT, there was unanimous consensus to implement a protein-restricted diet, pyridoxine, and/or dietary supplements to reduce and maintain plasma ornithine <400-500 µmol/L, while avoiding concentrations below the reference range. There was also strong agreement (9/10 respondents) to consider creatine supplementation for the prevention and/or treatment of secondary creatine deficiency.

Delphi 2 Survey

Respondents reporting experience with OAT (n=7) unanimously agreed that individuals with OAT should be prescribed the highest protein goal tolerated (typically 0.5-1.0 g total protein/kg/day) with EAA-based medical foods (typically 0.2-0.5 g/kg/day) to reduce dietary arginine intake, lower plasma ornithine concentrations, and slow the progression of retinal degeneration.

Lysine Supplementation

Consider lysine supplementation (e.g., 6-15 g/day) as an adjunct to dietary therapy in select individuals to enhance urinary ornithine excretion and further reduce plasma ornithine. A case report and case series described doses of 6-15 g lysine/day increased plasma lysine concentrations, lowered plasma ornithine by up to 30%, and increased urinary excretion of ornithine (F.4565, F.5890). However, lysine monotherapy has not been shown to normalize plasma ornithine.

Proline Supplementation

Proline supplementation is based on the hypothesis that OAT deficiency impairs proline synthesis, potentially depriving the retina, particularly the retinal pigment epithelium, of a key metabolic substrate. Case series suggest potential for stabilizing retinal function in some individuals, especially with early use and high doses (up to 10 g/day) (F.6517). However, evidence remains limited and inconclusive. More robust trials are needed to assess therapeutic benefit and guide clinical use.

Delphi 1 Survey

There was no consensus on the use of L-lysine supplementation in individuals who are unable to achieve target plasma ornithine levels through dietary restriction and pyridoxine alone with 5 of the 10 respondents neither agreeing nor disagreeing.

Proline supplementation was not included in the Delphi consensus process.