N-acetylglutamate synthase deficiency (NAGS)

NAGS deficiency is an ultra rare autosomal recessive urea cycle disorder that impairs carbamoyl phosphate synthetase I (CPS1) activation, resulting in hyperammonemia, particularly during infancy or illness. Clinical features range from neonatal coma and vomiting to developmental delay, feeding difficulties, and behavioral disturbances. Management aims to restore urea cycle activity, reduce ammonia, and ensure long-term metabolic stability.

Nutrition Management Recommendations for Individuals with NAGS Deficiency:

1. Prescribe an unrestricted protein diet for individuals with NAGS deficiency who are on an efficacious dose of carglumic acid.

2. Prescribe a sick day protocol with adequate energy intake and temporary protein reduction during acute illness when carglumic acid is not tolerated to prevent hyperammonemia. (See Recommendation 1.7 for additional information.)

3. Aggressively manage intercurrent illness/hyperammonemia with IV glucose/lipids similar to other proximal UCDs when cargluic acid is not tolerated or not available.

4. Use L-citrulline supplementation to replenish plasma concentrations, monitoring plasma citrulline and arginine to assess efficacy and guide dose adjustments.

Carbonic Anhydrase VA (CA-VA) Deficiency

Carbonic Anhydrase VA (CA-VA) is essential for the mitochondria to produce bicarbonate and maintain pH balance. CA-VA deficiency is an autosomal recessive disorder that typically presents in the neonatal period with a constellation of biochemical abnormalities, including hyperammonemia, metabolic acidosis, hypoglycemia, elevated blood lactate, ketonuria, and excretion of carboxylase-related metabolites. Acute treatment typically includes temporary protein restriction, nitrogen scavengers, and carglumic acid to support urea cycle function.

Nutrition Management Recommendations for Individuals with Carbonic Anhydrase VA (CA-VA) Deficiency:

1. Prescribe a sick day protocol with adequate energy intake and temporary protein reduction during acute illness. (See Recommendation 1.7 for additional information.)

2. Consider use of carglumic acid (50 mg/kg/d) to support metabolic stability.

Citrin Deficiency

Citrin deficiency results from mutations in the SLC25A13 gene, which encodes citrin, a mitochondrial aspartate-glutamate carrier critical for the proper function of the malate-aspartate shuttle. This impairment leads to an excessive accumulation of cytosolic NADH, which impairs gluconeogenesis and glycolysis. Citrin deficiency also reduces the availability of aspartate, which is essential for arginosuccinate synthesis, thereby impairing normal urea cycle function and leading to hyperammonemia and its sequelae. Nutrition management of citrin deficiency, spanning neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in infancy to adult-onset type II citrullinemia (CTLN2), is based on addressing the underlying disturbances in energy metabolism and the urea cycle due to impaired functioning of the citrin transporter.

A primary nutrition intervention is the avoidance of carbohydrate-rich diets. High carbohydrate intake exacerbates cytosolic NADH accumulation within hepatocytes deteriorating the metabolic state. Protein recommendations are generally provided in recommended macronutrient distributions (detailed below) rather than in grams per kilogram body weight. General principles of nutrition management include:

• Avoid high carbohydrate exposure including IV glucose infusions, high-carbohydrate oral supplements, and concentrated sweets, as these may precipitate severe metabolic decompensation.
• Encourage dietary patterns that align with the characteristic preferences for protein- and fat-rich foods observed in individuals with citrin deficiency, and educate individuals and families on monitoring for signs of clinical recurrence.

Nutrition Management Recommendations

For Infants with NICCD

1. Provide a lactose-free infant formula to prevent and/or treat cholestasis and liver dysfunction; and consider discontinuing dietary lactose restriction after 12 months of age once liver function tests have normalized.

2. Provide an MCT-enriched infant formula (containing approximately 30-50% of total fat as MCT) or MCT oil supplementation to support energy metabolism while bypassing NADH-dependent pathways.

3. Supplement fat-soluble vitamins (A, D, E, and K) to support liver health.

4. Consider providing ursodeoxycholic acid in infants experiencing cholestasis to support liver health.

5. Continue regular clinical and biochemical monitoring (e.g., ammonia, citrulline, liver function tests), especially during illness, dietary changes, or metabolic stress.

For Older Children and Adults (CTLN2)

1. Aim for a high protein, high fat diet with the following macronutrient distribution (as percentage of total energy intake): Protein: 15-30%; Fat: 40-50%; Carbohydrate: 30-40%.

2. Consider supplementing with MCT oil to support energy metabolism while bypassing the impaired cytosolic NADH-dependent pathways.

Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome

HHH syndrome is a rare inherited disorder of ornithine transport, characterized by hyperornithinemia, hyperammonemia, and homocitrullinuria. Clinical presentations vary but often include developmental delay, seizures, protein aversion, liver dysfunction, and neurocognitive impairment. Management of HHH Syndrome centers on controlling ammonia concentrations, optimizing protein intake, and supporting metabolic stability.

Nutrition Management Recommendations for Individuals with HHH Syndrome:

1. Individualize the protein prescription, titrating to the highest protein intake tolerated while maintaining metabolic stability. See TABLE #2, Monitoring the Nutritional Management of an Individual with UCD when Well for typical protein and energy recommendations.

2. Supplement with L-citrulline (100-250 mg/kg/d) to support metabolic stability.

Lysinuric Protein Intolerance

Lysinuric Protein Intolerance (LPI) is an inherited disorder of cationic amino acid (lysine, arginine, and ornithine) transport at the basolateral membrane of intestinal and renal tubular cells and associated with a range of multisystem clinical findings. Nutrition management of LPI focuses on individualized protein restriction to reduce ammonia accumulation while supporting growth and preventing essential amino acid deficiencies.

Nutrition Management Recommendations for Individuals with LPI:

1. Individualize the protein prescription, titrating to the highest protein intake tolerated while maintaining metabolic stability. Typical intakes range from 1-1.5 g/kg/day in infants and children and 0.8-1 g/kg/day in adults. See TABLE #1, Total Protein and Energy Recommendations for Individuals with Urea Cycle Disorders When Well for typical protein and energy recommendations.

2. Use L-citrulline (dosed at approximately 100-170 mg/kg/day divided) as first-line supplementation to help support the urea cycle and replenish plasma arginine and ornithine. Monitor plasma amino acids to assess efficacy. See TABLE #2, Monitoring the Nutritional Management of an Individual with UCD when Well for frequency.

3. Evaluate renal function using creatinine, cystatin C, and urinalysis at least once annually due to the high risk of progressive kidney disease in LPI.

Ornithine aminotransferase (OAT) deficiency

Nutrition management for ornithine aminotransferase (OAT) deficiency, also know as gyrate atrophy (GA), focuses on lowering plasma ornithine levels to slow the progression of retinal degeneration. The primary strategies include use of a protein-restricted diet with EAA-based medical foods to reduce arginine intake, and, in some cases, supplementation with pyridoxine or L-lysine. These interventions vary in efficacy and patient tolerability, and long-term adherence remains a challenge.

Nutrition Management Recommendations for Individuals with Ornithine Aminotransferase (OAT) Deficiency:

1. Individualize the protein prescription, titrating to the highest protein intake tolerated while maintaining metabolic stability (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.

2. Trial pyridoxine (typically 300 mg/day) in all patients with OAT to evaluate responsiveness, given the potential for 25-50% reduction in plasma ornithine in responders.

3. Continue pyridoxine supplementation only in responders, as most patients are non-responsive and derive no benefit from ongoing use.

4. Consider creatine monohydrate supplementation (e.g., 1.5-2.0 g/day divided, or for children 0.25 g three times daily) to correct secondary creatine deficiency and improve skeletal muscle histology and energy metabolism.

5. Aim to maintain plasma ornithine concentrations below 500 µmol/L while avoiding concentrations below the lower limit of the reference range, as concentrations below this threshold have been associated with stabilization of retinal function.