Energy intake in individuals with UCDs must be carefully prescribed to prevent catabolism, support growth, and maintain metabolic stability. Adequate non-protein energy is essential to achieve a protein-sparing effect, allowing amino acids to be used primarily for protein synthesis rather than as an energy source (F.7802). EAA-based medical foods, protein-free medical foods, and low-protein energy sources play a key role in meeting these needs and supporting metabolic stability (F.7802).

Energy prescriptions for individuals with UCDs generally approximate those recommended for healthy populations. Physical activity should be evaluated and encouraged to support fat-free mass (FFM) (F.4826), and energy needs should be adjusted for activity level, as those with lower physical activity may have reduced energy requirements (F.7963). Additionally, indirect calorimetry data showed decreased resting energy expenditure among individuals with UCDs, particularly those with ASA, highlighting the need for tailored energy prescriptions (F.7968).

Reported energy prescriptions across UCD subtypes generally align with or slightly exceed protein needs based on the DRIs or FAO/WHO/UNU 2007, with adjustments made for age and physical activity (F.7963, F.7964). Longitudinal data from the E-IMD registry showed that prescribed energy among pediatric UCDs averaged 105 ± 28 % of the Recommended Dietary Allowance (RDA) (F.7964). A multicenter study of 361 children and adults similarly found that prescribed energy intakes were consistent with or slightly above reference standards (F.7965). In contrast, pooled data from glycerol phenylbutyrate clinical trials (n = 94) demonstrated that reported mean adult energy intakes (approximately 1,900-2,200 kcal/day) represented 78-79% of the RDA and 86-92% of National Health and Nutrition Examination Survey (NHANES) estimates, whereas pediatric intakes (range 43-101 kcal/kg/day) more closely aligned with RDA and NHANES data (F.7972). In another large cohort, early-onset cases had higher energy intakes than late-onset cases, though mean intakes remained below FAO recommendations (F.4803).

The balance between protein and energy has also been examined through the protein-to-energy (P:E) ratio. Stable growth outcomes (i.e., z-scores of 0±1) have been reported when protein provides approximately 6-12% of total dietary energy or a P:E ratio of >1.5 to <2.9 g protein/100 kcal (F.7970). Longitudinal data from 311 individuals with UCDs in the E-IMD registry showed a median total P:E ratio of 1.42 (range: 0.53–3.53) and median natural P:E ratio of 1.19 (range: 0.47-2.71). Height-for-age z-score was positively associated with the natural P:E ratio (β = 0.224, p = 0.036) (F.7964). Among adults with UCDs, mean protein contributed about 10% of total energy intake compared with approximately 15% in a healthy population based on NHANES data, reflecting greater dependence on non-protein energy sources (F.7972).

Delphi 1 Results

Respondents reached consensus that, when clinically well, individuals with UCDs generally require 80-120% of the energy DRI (96% agreement), and that increasing energy intake up to 120% of DRI may be necessary to achieve or maintain normal growth and metabolic stability (87%).

There was no consensus (79%) that some individuals may require less than the DRI for energy due to lower resting energy expenditure or physical inactivity.

Protein goals for individuals with UCDs are generally based on U.S. DRIs or FAO/WHO/UNU guidelines and then individualized based on age, disease severity, clinical status, and anthropometric and biochemical monitoring (F.7963, F.5648, F.4783). Reported requirements for UCDs typically fall within or slightly below recommendations for healthy individuals (F.6480, F.5648, F.7965). Across numerous case reports, most individuals tolerate 1.0-1.5 g total protein/kg/day (F.6648, F.7286, F.4776, F.7961, F.5794, F.6816, F.4691, F.5322, F.7941, F.6961, F.6804, F.5501, F.5525, F.7960, F.6481). Those with severe phenotypes often require more stringent intact protein restriction and greater reliance on EAA-based medical foods (F.7964, F.4674, F.4691, F.5203, F.5623, F.4640), whereas individuals with milder or late-onset disorders may tolerate 1.5-2.0 g/kg/day or more with careful monitoring (F.4822, F.7284, F.5778, F.5422, F.6132, F.4691). Several reports also describe self-imposed restriction, particularly among late-onset adults (F.4858, F.4948, F.7174). Although excessive protein intake increases the risk of decompensation, over-restriction has been associated with poor growth and dermatologic manifestations that improve with targeted amino acid supplementation or dietary liberalization (F.6865, F.5006, F.7139). In some individuals with obesity (BMI >30), clinicians may consider estimating protein needs using ideal or adjusted body weight as part of individualized assessment, with the goal of aligning protein provision more closely with lean body mass. Because protein tolerance varies substantially and fluctuates across the lifespan, nutrition prescriptions must be continually adjusted—especially during infancy, rapid growth, puberty, pregnancy, illness, or metabolic stress—when needs may temporarily increase and adherence may be more challenging (F.4691, F.5620, F.6373).

0 to 12 Months

Reported protein prescriptions for infants 0-12 months with UCDs vary widely from 0.9 g/kg/day to 2.2 g/kg/day, reflecting substantial variability in tolerance. Intakes of approximately 1.0-1.5 g/kg/day were frequently reported in infancy (F.5915, F.6602, F.7286, F.7941, F.7961), including 1.0 g/kg/day supporting normal growth at 12 months (F.7286) and improved biochemical stability when reducing intake from 1.5 to 1.2 g/kg/day in another infant (F.7961). Some infants demonstrated higher protein tolerance, including approximately 2 g/kg/day in a 6-month-old with late-onset OTC (F.5422), 2.2 g/kg/day in infants with ASA (F.4858), and 1.8-2.0 g/kg/day in another infant with ASA to address poor growth (F.6861). Others maintained stability on lower intact-protein intakes, such as 0.9-1.4 g/kg/day (F.5946). Among infants with lower protein tolerance, use of EAA-based medical foods was often needed to support metabolic stability and age-appropriate growth, with reported regimens including 0.7 g/kg/day intact + 0.5 g/kg/day EAA with normal development at 9 months (F.5915) and approximately 1 g/kg/day intact protein + 1 g/kg/day EAA in early CPS management (F.5982). Expert sources similarly recommend a broad range of infant protein goals, from 0.9-2.2 g/kg/day (F.7801, F.7802) and 1.2-2.2 g/kg/day for UCDs overall (G.193), with one source specifying 1.5-2.0 g/kg/day for CIT-I and ASA and 0.7 g/kg/day intact + 0.7 g/kg/day EAA for CPS, OTC, and ARG (F.4691). Another expert opinion notes that protein needs during early infancy may approach 1.8-2.0 g/kg/day, particularly during periods of rapid growth (F.5650). Multinational survey data reflect this variability. For infants 0-6 months of age, median total protein goals were 1.6 g/kg/day for OTC (range 1.0-2.2), 1.7 g/kg/day for CIT-I (range 1.0-2.5), 1.8 g/kg/day for CPS (range 1.0-2.2), 1.9 g/kg/day for ASA (range 1.6-2.5), and 2.0 g/kg/day for ARG (range 1.7-2.5). For infants 7-12 months of age, median goals were 1.6 g/kg/day for OTC (range 1.1-2.2), 1.6 g/kg/day for CIT-I (range 1.1-1.8), 1.3 g/kg/day for CPS (range 0.9-1.9), 1.6 g/kg/day for ASA (range 1.2-2.4), and 1.6 g/kg/day for ARG (range 1.5-1.8) (F.4514). Overall, the most typical protein intakes reported for infants cluster between approximately 1.0 and 2.0 g/kg/day.

1 to 8 Years

Across the available literature, prescribed or reported protein intakes for children 1-8 years of age with UCDs generally fell between 1.0 and 1.5 g/kg/day, with variation by disorder, age, and clinical status. Expert opinion similarly recommends protein goals of 1.0-1.2 g/kg/day for children 1-7 years of age (G.193), aligning with the lower end of these reported ranges. In toddlers with OTC, case reports described metabolic stability and normal growth on 1.0-1.5 g/kg/day (F.7286) and 1.5-1.7 g/kg/day at 12-18 months (F.7284). Additional reports noted tolerance of 1.3-1.4 g/kg/day with ~45% EAA through 3.5 years in a female heterozygote (F.7960) and maintenance of metabolic control on 1.6 g/kg/day with 30% EAA through 30 months in a male with early-onset OTC (F.4824). In a larger retrospective cohort, children with early-onset OTC were typically prescribed 1 g/kg/day from 1-6 years, whereas those with late-onset OTC tolerated mean intakes of 1.3 g/kg/day at 1 year, 1.1 g/kg/day at 3 years, and 0.9 g/kg/day at 6 years (F.4776). In ASA, reported protein intakes generally ranged from approximately 1.2-1.4 g/kg/day (F.5322, F.6953). Some children required 1.8-2.0 g/kg/day to support growth (F.6861), and another report described goals of 1.5 g/kg/day at 13 months and 1.0 g/kg/day at 7 years (F.5794). For CIT-I, prescriptions of 1.75 g/kg/day were reported for a child aged 1-3 years (F.7708). Survey data from European centers further documented median prescriptions for 1- to 10-year-olds of 1.3 g/kg/day for OTC (range 0.7-2.1), 1.1 g/kg/day for CIT-I (range 0.7-1.5), 1.1 g/kg/day for CPS (range 0.6-1.6), 1.3 g/kg/day for ASA (range 0.6-2.5), and 1.3 g/kg/day for ARG (range 0.9-1.5) (F.4514). Overall, children aged 1-8 years with UCDs are most commonly managed with total protein intakes of 1.0-1.5 g/kg/day, with younger children typically tolerating higher relative intakes and older children requiring lower amounts over time.

9 to 18 Years

Across the limited literature describing protein prescriptions for children and adolescents 9-18 years of age with UCDs, reported intakes generally aligned with the expert opinion recommendation of 0.8-1.4 g/kg/day for those 8-19 years of age (G.193), though ranges varied by disorder and source. In a newborn-screened cohort of 13 individuals with ASA, older children and teenagers were typically prescribed 1.0 g/kg/day, with some also receiving EAA-based medical food and generally demonstrating normal growth (F.5126). A case report of a 16-year-old with late-onset CIT-I described successful metabolic control on 1 g/kg/day (F.6804). More detailed, adolescent-specific data came from a European dietitian survey (F.4514), which reported median prescribed intakes for 11- to 16-year-olds of 0.9 g/kg/day for OTC (range 0.5-1.7), 0.8 g/kg/day for CPS (0.7-0.8), 0.9 g/kg/day for CIT-I (0.5-1.5), 1.3 g/kg/day for ASA (0.6-2.5), and 1.3 g/kg/day for ARG (0.9-1.5), with most values falling within or near the expert-recommended range. Overall, the available evidence for ages 9-18 remains sparse, but prescribed protein intakes across sources generally fall within 0.8-1.4 g/kg/day, with higher intakes observed in select contexts.

>18 Years

Across the available literature, protein goals and intakes for adults >18 years of age with UCDs varied widely. In a large retrospective OTC cohort (F.4776), 75% of late-onset adults (>16 years) were not placed on a defined low-protein diet and self-restricted protein to approximately 35-50 g/day, which corresponds to roughly 0.6-0.8 g/kg/day for a 60-kg woman and 0.5-0.7 g/kg/day for a 70-kg man. Additional case-based evidence included a 37-year-old woman with OTC who maintained metabolic stability on 0.8 g/kg/day (F.7174), and a 32-year-old woman with late-onset OTC who consumed 0.5-0.7 g/kg/day during the year following a severe hyperammonemic episode (F.4948). Survey data from European metabolic centers (F.4514) provided the most detailed adult-specific prescriptions, reporting median intakes for individuals >16 years of 0.8 g/kg/day for OTC (range 0.4-1.7), 0.7 g/kg/day for CIT-I (0.4-1.2), 0.8 g/kg/day for CPS (0.6-1.0), 0.8 g/kg/day for ASA (0.3-1.3), and 0.8 g/kg/day for ARG (0.7-0.9). Taken together, adult prescriptions across studies varied widely, yet most reported values and clinical practice patterns clustered around 0.7-1.0 g/kg/day for long-term management, which is consistent with expert-opinion guidance recommending 0.8-1.0 g/kg/day for adults >19 years with UCDs (G.193).

Delphi 2 Results

Respondents strongly agreed (96%) that protein prescriptions should reflect the highest protein intake an individual can tolerate, generally within the range of 0.8-1.5 g/kg/day.

There was also strong consensus (96%) that individuals with mild UCD typically tolerate a protein-controlled diet or even unrestricted protein diet.

Consensus (88-92%) was reached for the following age-specific total protein intake ranges that are typically tolerated by individuals with UCDs:

• 1.1-2.2 g/kg/day for 0-12 months
• 1.0-1.3 g/kg/day for 1-8 years
• 0.8-1.4 g/kg/day for 9-18 years
• 0.7-1.0 g/kg/day for >18 years

For individuals with obesity, there was unanimous agreement to consider using ideal or adjusted body weight to estimate protein requirements, aligning protein goals more closely with lean body mass.

EAA-based medical foods vary in composition; some are nutritionally complete and provide additional energy, fat, carbohydrates, and micronutrients, whereas others provide only EAAs and require remaining nutrients to be supplied from other dietary sources.

Use of essential amino acids in UCDs, provided via EAA-based medical food(s), is often implemented due to inadequate intact protein tolerance, low plasma EAA concentrations, and/or poor metabolic control (F.4514, F.4783). In individuals with severe UCD phenotypes, the degree of necessary dietary protein restriction may compromise growth (F.4691), and protein aversion may further limit intake of prescribed intact protein (F.4756). Observational data also indicate that protein-restricted diets and sodium phenylbutyrate are associated with lower plasma BCAA concentrations, and that plasma leucine or valine concentrations are positively associated with linear growth in certain UCD subtypes (F.7964). Low plasma BCAA concentrations have been associated with metabolic decompensation and are important for neurologic and mitochondrial function (F.7964). Accordingly, the balance between intact protein and EAA-based medical food is typically adjusted over time based on laboratory monitoring (e.g., plasma amino acids, ammonia), clinical status, and growth outcomes to avoid both amino acid deficiencies and excessive nitrogen burden.

EAAs provide adequate precursors for protein synthesis while limiting the nitrogen burden to the urea cycle, as they deliver a higher biological value of protein and contain a lower proportion of nitrogen than intact proteins (approximately 8.5-13.7% vs. 13.4-19.1% nitrogen) by limiting intake of non-essential amino acids (F.4783, F.5650). Additional theoretical benefits include the utilization of circulating ammonia in the synthesis of nonessential amino acids from EAAs, potentially further reducing the nitrogen load (F.4783, F.5648).

Use of EAA-based medical foods among individuals with UCDs varies widely by UCD subtype, disease severity, and clinical context, with the goals of preventing amino acid deficiencies, avoiding sequelae of protein over-restriction, and maintaining metabolic stability during periods of increased vulnerability. A European clinician survey and E-IMD patient registry data reported use of EAA-based medical foods in 38-39% of the UCD patient population, with EAA use more common among individuals with early-onset disease (62%) compared with late-onset disease (29%) (F.4514, F.4803). Rates of EAA use also differed by center and country, reflecting variability in clinical practice and/or access to EAA-based medical foods (F.4514, F.4783). Comparable survey or registry data are not available for UCD populations treated in the United States.

Expert opinion, clinical practice papers, and clinical protocols generally recommend that EAAs provide approximately 20-30% (F.4783, F.7963), 25-50% (F.5648, F.7801), 40-60% (G.187), or 50-60% of total protein intake in UCDs overall (F.7802) and approximately 50% of total protein recommended in CPS, OTC, and ARG (F.4691). Although protein prescriptions varied, reported proportions of total protein provided as EAAs typically ranged from 30% to approximately 50% (F.4514, F.4783), with higher percentages more often used in individuals with severe disease.

Case studies and registry data further describe the proportion of total protein provided as EAAs across UCD subtypes. Case reports of children included EAA intakes of 42-50% in CPS (F.5915, F.5982), 30-45% in OTC (F.4824, F.7960), 17-54% in CIT-I (F.7708, F.7802), and approximately 40% in ASA (F.5501). European registry data reported median (range) EAA prescriptions across age groups of 38-50% (10-80%) of total protein in CPS, 14-39% (13-60%) in OTC, 25-50% (12-90%) in CIT-I, and 29-51% (10-69%) in ASA (F.4514). However, many publications referenced the use of EAA-based medical foods without specifying exact quantities.

Delphi 1 Results

When considering the source of protein in the diet, respondents agreed (88%) that for severe UCDs, EAA-based medical food should be prescribed, and EAAs generally should not exceed 50% of the total protein goal.

There was also consensus (88%) that EAA-based medical foods may exceed 50% of the total protein goal if the individual had elevated plasma glutamine with low plasma BCAA and total protein was at the DRI or there was elevated glutamine with low plasma EAA and total protein was at the DRI.

When asked what the next step would be if plasma BCAA were low on two consecutive samples and glutamine is <900 µmol/L, there was strong consensus (96% agreement) with increasing protein from EAA-based medical food, and 91% agreement with increasing protein from high biological value sources.

There was unanimous agreement that, if plasma glutamine is elevated (>900 µmol/L) and plasma EAAs are low, it is appropriate to proportionally increase EAA-based medical food and decrease intact protein.

Respondents further agreed (92%) that in mild UCDs, use of EAA-based medical food is generally not required.

Delphi 2 Results

For individuals with severe UCDs, there was unanimous agreement to use EAA-based medical food to provide approximately 50% of total protein needs, with titration as clinically indicated.

Reports consistently show that individuals with ARG are treated with low protein diets in which 40-78% of total protein is supplied as EAA-based medical food, which provide an arginine-free source of protein. In a 2022 case series, EAA proportions ranged from 40-62.5%, and early treatment was associated with normal neurodevelopment, whereas later-diagnosed individuals developed spastic paraparesis or seizures (F.4535). Additional reports described biochemical and clinical improvements on high-EAA diets, including a 9.5-year-old who demonstrated lower plasma arginine and guanidino compounds and cognitive gains when ~60% of her protein was transitioned to EAAs (F.5583), and two individuals receiving 72-78% EAAs who showed marked reductions in guanidino compounds, with near-normalization in a 17-year-old (F.5793). An infant treated initially with 100% EAAs (2 g/kg/d), then 75% (2 g total protein/kg/d) and ~67% (1.5 g total protein/kg/d), achieved good metabolic control and normal neurologic development, but growth remained below the 3rd percentile (F.4772).

Broader observational and survey data further support extensive EAA use in ARG. One study showed that 0.4-0.7 g/kg/day of EAAs, with or without sodium benzoate, reduced arginine and guanidino compounds more effectively than intact protein restriction alone (F.5790). A survey of 19 individuals found mean natural and total protein intakes of 0.82 and 1.25 g/kg/day, respectively, indicating use of EAAs (F.7342). Additionally, a UK practice survey reported that 30% of individuals with UCDs received 10-65% of their total protein from EAAs, with those with ARG receiving a higher proportion than other UCD subtypes (F.4783). Despite these benefits, a 2022 systematic review concluded that routine therapy including dietary arginine restriction, typically with use of EAAs, often fails to fully normalize arginine or halt neurologic progression in ARG (F.4728). These findings suggest that, while low protein diets with ~40-78% of total protein as EAAs can meaningfully improve metabolic control, achieving target arginine concentrations remains difficult even with aggressive dietary management.

Delphi 1 Results

There was no consensus reached with the recommendation to increase EAA-based medical food above 50% total protein for an individual with ARG with an arginine >200 µmol/L.

Delphi 2 Results

For individuals with ARG, there was consensus (87%) to provide approximately 50% of total protein as intact protein and titrate based on plasma arginine concentrations, proportionately adjusting EAA-based medical food as needed.

When individuals are unable or unwilling to consume EAA-based medical foods, incorporating high biological value (HBV) protein sources (e.g., animal proteins) may offer a nutritional advantage. HBV proteins provide all essential amino acids in proportions that closely align with human requirements and are efficiently digested and utilized, potentially allowing essential amino acid needs to be met with a lower total protein intake. However, HBV protein sources are typically protein-dense, such that even small portions may contribute a substantial amount of total protein; therefore, careful selection of HBV foods and close monitoring of intake are important to avoid exceeding prescribed protein goals.

Expert guidance emphasized that dietary protein is ideally derived from a combination of low biological value proteins with some HBV proteins to ensure adequate EAA intake, as some lower biological value protein sources are limited in specific EAAs (F.7963). The authors further noted that use of select HBV protein sources, rather than exclusive reliance on EAA-based medical food, may improve palatability and quality of life, although EAA use is necessary for some individuals to maintain metabolic stability (F.7963). In situations where EAA-based medical foods are not prescribed or are unavailable, additional expert guidance recommended that a substantial proportion of total protein intake (e.g., approximately half) may be derived from HBV protein sources to support essential amino acid adequacy (G.187).

Delphi 2 Results

For individuals who failed a trial of EAA-based medical food and who exhibit low plasma EAAs, there was strong agreement (96%) to consider strategic introduction of up to 50% of the total protein goal from high biological value protein sources.

Human milk feeding (HMF) is associated with reduced infectious morbidity, improved neurodevelopmental outcomes, and optimal support of immune development during early life (L.456, L.465). In healthy infants, human milk (HM) is recommended as the preferred source of nutrition, with exclusive breastfeeding encouraged for approximately the first six months of life and continued breastfeeding alongside complementary foods thereafter (L.456).

In contrast to the general population, the use of HMF in infants with UCDs requires additional consideration and individualized management. When closely monitored, HMF may be safely used in selected cases, particularly incorporated into structured feeding regimens designed to limit total protein intake while ensuring adequate energy intake, such as through use of protein-free medical food or energy modules (F.6373, F.7802, G.193). Human milk provides adequate EAAs despite its lower total protein content compared with standard infant formula, which may offer a nutritional advantage for infants with UCDs requiring protein restriction (L.465). Nevertheless, use of HMF in UCDs introduces practical challenges that may inadvertently affect metabolic stability (F.5749). As a result, early case reports and expert opinion have highlighted a lack of consensus regarding exclusive, on-demand breastfeeding in severe phenotypes such as OTC and CPS (F.5749, F.6553, F.7802), with expert guidance favoring the use of expressed human milk to allow precise control of feeding volume and protein intake (F.7802). Consistent with this approach, the 2012 European UCD guidelines support structured feeding regimens, noting that exclusive on-demand breastfeeding may be feasible only with careful monitoring and recommending provision of a protein-free medical food prior to breastfeeding when protein restriction is necessary (F.6373).

Evidence describing HMF in infants with UCDs remains limited and largely observational, with reports noting variable practices and mostly favorable short-term outcomes. A 2006 international survey reported that 22% of centers used on-demand breastfeeding for OTC/CPS and 30% for ASA/CIT-I, typically in combination with a protein-free medical food, and emphasized the importance of early and consistent lactation support to address maternal anxiety, inexperience, and infant feeding challenges (F.5749). Additional case reports also describe positive HMF outcomes; in three documented UCD cases (two ARG, one OTC), infants received HMF for an average of 5.5 months without metabolic crises, with normal neurodevelopment and growth, and weaning due to age or reduced milk supply (F.6930). In another report, an infant with ARG diagnosed on newborn screening received HMF supplemented with protein-free calories from 3-6 months of age without complications (F.4556). More recently, a 2025 systematic review reported HMF among 14 infants with UCDs (including two infants described above in F.6930), with feeding durations ranging from 1.5 to 9 months. The authors reported successful use of exclusive HMF in six infants with UCDs (one CPS, three OTC, and two ARG), with adequate growth observed in nine of ten infants and acceptable metabolic control in 11 of 12 infants receiving either HMF exclusively or in combination with medical food (L.465).

When HMF is used in infants with UCDs, close monitoring of maternal milk supply, infant growth, and metabolic control are essential. In the United States, HMF initiation rates are high in the general population, yet exclusive HMF declines over time, with approximately 46% of infants exclusively breastfed at 3 months, 26% at 6 months, and only about 35% receiving any human milk at 12 months. Early infant formula supplementation is also common, occurring in roughly 19% of HM-fed infants within the first 48 hours of life due to a variety of clinical and practical factors (L.456). For families affected by UCDs, additional stressors from the diagnosis, hospitalizations, and daily disease management may further challenge maintenance of human milk supply. These patterns highlight the need for clinician guidance and anticipatory planning for access to infant formula and/or protein-free medical food and its incorporation into the nutrition prescription if indicated.

While human milk offers recognized immunologic and developmental benefits and is considered the normative standard for infant feeding (L.456, L.465), its use in UCDs requires individualized assessment based on maternal preference, availability, disease severity, metabolic stability, and the ability to closely monitor protein intake. Multidisciplinary coordination and early feeding support remain essential to ensure safe and effective nutrition management during infancy (F.5749).

Delphi 1 Results

In a clinically well infant with mild UCD, there was unanimous agreement that it is appropriate to encourage and support breastfeeding if desired and near unanimous agreement (96%) that human milk (expressed or fed at the breast) should be considered as the sole source of protein if supply is adequate. However, six respondents disagreed with this statement when considering an individual with severe UCD.

Encouragement of some breastfeeding for a severe UCD almost met the level of agreement (75%). There was consensus that if an infant fed human milk does not meet weight gain goals, supplementation with a protein-free medical food is warranted.

Delphi 2 Results

There was consensus (87%) to use human milk as a sole or primary source of protein in infants with mild or severe UCD.

There was unanimous agreement to consider using expressed human milk in infants with severe UCD.

Tube feeding is an essential component of UCD management to maintain nutritional adequacy, enable medication delivery, and support metabolic stability when oral intake is inadequate. Enteral nutrition, via short-term nasogastric (NG) or long-term gastrostomy (G) tubes, is advised in cases of feeding difficulties, inadequate oral intake, or early-onset/severe phenotypes to maintain reliable nutrient and energy delivery (F.7963). Consensus papers and case studies highlight G-tubes as effective for improving dietary adherence in young children and those with ongoing oral intake challenges (F.7802, F.6564, F.4824). Two older case studies also described the benefit of nocturnal G-tube or NG-tube feeds to reduce daytime feeding burden, support growth, and promote oral intake during the day (F.4824, F.5793).

Behavioral feeding difficulties, including anorexia and food refusal, are common in individuals with UCDs and may increase tube feeding reliance. An analysis of de-identified plasma samples suggested those with UCDs have higher plasma concentrations of the neuroendocrine hormone peptide tyrosine tyrosine (PYY), offering a potential biological explanation for reduced appetite in this population (F.6357). Regardless of whether an organic cause is present, behavioral feeding interventions can promote oral intake, decrease tube dependence, and improve feeding behaviors (F.6564). In one survey of metabolic dietitians, 18% of individuals with UCDs were prescribed a feeding tube for nutrition support and an additional 3% used them solely for medication delivery (F.4514). These findings were consistent with a prospective study of 456 individuals with UCDs in Europe and Asia, in which 8% required tube feeding; notably, 72% of these were early onset cases (F.4803). The use of g-tubes for medication delivery was also highlighted in the 2019 European guidelines (F.7963). Successful tube feeding management requires caregiver education and ongoing assessment of feeding strategies (F.7802).

Delphi 1 Results

There was strong agreement (88%) that for all infants or children with severe UCDs, a gastrostomy tube should be considered to provide adequate nutrient and fluid intake and administer medications.

There was unanimous agreement that, for those WITH a feeding tube, individuals should be referred for feeding evaluation and therapy to support development of age-appropriate feeding behaviors, and caregivers should be encouraged to offer age- appropriate oral food and foster development of normal eating behaviors, in addition to proving enteral feedings.

Vitamin and mineral supplementation may be needed in individuals with UCDs to prevent deficiencies that may arise due to limited protein intake. A protein-restricted diet may increase risk for deficiencies of iron, zinc, copper, calcium, and vitamin B12 (F.7963). Expert opinion and 2019 European guidelines indicate to supplement or consider supplementing vitamins and minerals (F.7963), particularly for individuals who do not consume medical foods with added micronutrients (F.5620, F.6480, F.7801). One expert opinion suggested vitamin and mineral supplementation may not be required when an EAA-based medical food provides 50-60% of the individual's prescribed protein (F.7802). Other publications highlight the importance of monitoring nutrient intake (e.g., some EAA-based medical foods lack essential vitamins and minerals) and adherence to diet prescriptions (F.7802, F.7963), which can guide the need for vitamin and mineral supplementation. See Recommendation 3.1 for considerations regarding nutrition assessment and Recommendation 3.3 and TABLE #2, Monitoring the Nutritional Management of an Individual with UCD when Well for guidance on biochemical monitoring for nutrient deficiencies.

Carnitine supplementation has been reported in UCDs. Case studies (1990-2019) have shown that L-carnitine supplementation (10-100 mg/kg/day) can treat/prevent secondary carnitine deficiency and/or lower plasma ammonia (F.6603, F.6075, F.4556, F.7082). While these case reports support the use of carnitine in select cases (e.g., those with secondary carnitine deficiency), there are no published data to support the utility of long-term carnitine supplementation in UCD management.

Overall, individualized supplementation based on nutrient intake and biochemical monitoring is necessary to prevent nutritional deficiencies and optimize outcomes in individuals with UCDs.

Delphi 2 Results

There was unanimous agreement to regularly monitor dietary intakes of micronutrients (particularly calcium, copper, iron, selenium, vitamin B12, vitamin D, and zinc) and essential fatty acids and supplement as needed. See Recommendation 3.3 for consensus findings related to biochemical monitoring.

Proper hydration is another critical component of metabolic stability. Dehydration has been noted as a trigger for hyperammonemia, particularly in infants and young children (F.7802). Adequate fluid intake should be based on energy consumption, with infants requiring at least 1.5 mL of fluid per kcal, and this reduces to 1.0 mL/kcal after the first year of life into adulthood (F.7801, F.7802).

Delphi 2 Results

There was also consensus to ensure adequate fluid intake (e.g., ≥ 1.5 mL/kcal/day for infants and ≥ 1.0 mL/kcal/day in older children).

Specific recommendations regarding anesthesia precautions and prolonged fasting in UCDs are limited to expert opinion and a few single case reports. A 2016 case report described use of nitrogen scavengers preoperatively and a strong preference for minimally metabolized, short-acting anesthetic agents that reduce stress and neuroendocrine activation (e.g., catecholamines and cortisol), thereby limiting ammonia generation during surgery (F.6868). Another case report outlined the center's protocol to include close intraoperative monitoring, IV nitrogen scavengers, continuous glucose infusion (10-15 g/kg/day), and attention to fluid status to avoid both dehydration and osmotic diuresis due to hyperglycemia (F.7720). Authors recommended individuals with UCDs be prioritized to be first on the surgical schedule to minimize fasting time (F.7720, F.7963).

Preoperative planning emphasizes early hospital admission, ideally the day before surgery (F.4691, F.7720, F.7963). This allows time for evaluating baseline plasma ammonia and amino acid levels, ensuring the individual is not decompensated before undergoing anesthesia. For individuals who are fasting preoperatively, intravenous fluids containing glucose (typically 10%, with one case report utilizing 5% in an adolescent) and electrolytes are recommended to maintain anabolic metabolism and prevent catabolism (F.4691, F.7963, F.7720, F.6868). For longer surgeries, lipid emulsion or total parenteral nutrition may be added to supply additional calories and mitigate protein breakdown (F.4691). Medication regimens should continue uninterrupted, with necessary conversions from oral to intravenous administration as patients become NPO (F.7963, F.7720). Finally, procedures should ideally be conducted in specialized centers with metabolic expertise and emergency protocols for hyperammonemia, ensuring optimal outcomes and safety (F.7963).

Special cases, including religious fasting and fasting in conjunction with intense exercise, highlight the risks of prolonged fasting, which can precipitate hyperammonemic crises and should be avoided (F.5787, F.5625).

Delphi 1 Results

There was unanimous agreement with the following statements:

1. Individuals should receive adequate energy via continuous IV dextrose, and if indicated, lipid emulsion to minimize/prevent catabolism.

2. The metabolic team should try to coordinate a first-of-the-day procedure time to limit fasting duration.