Comprehensive nutrition evaluation in individuals with UCDs incorporates dietary history (e.g., diet record, 24-hr recall, food frequency questionnaire, typical intake patterns), nutrient analysis, nutrition-focused physical exam (NFPE), growth monitoring, physical activity, feeding skills, and laboratory results to assess nutritional adequacy and adherence to diet prescriptions. Three-day diet records are preferred over single-day recalls for capturing intake variability, particularly in children (F.7801, F.7802). Routine assessments of dietary intake are essential for identifying and/or preventing excessive protein restriction or aversion, which can lead to metabolic instability (F.6373), as well as excess protein intake, which is common among some individuals (F.6122). Furthermore, nutrient intake should be correlated with plasma amino acid concentrations to assess the metabolic impact of dietary intake and to adjust diet prescriptions accordingly (F.7802)​.

Protein aversion, severe disease, and nutritional/pharmacological management contribute to risk of protein deficiencies in UCDs. It is common for individuals to consume less protein than tolerated (F.4756). A retrospective review of 90 individuals identified protein aversion as a major challenge both before and after diagnosis (F.4952), a finding reinforced in a case series of two siblings with ARG (F.6648). Inadequate protein intake can impair growth, metabolic stability, and overall health, necessitating individualized adjustments based on tolerance and metabolic control (F.6373, F.4756). A 2022 study of 18 adults with either UCDs (12/18) or organic acidemias (6/18) using a seven-day weighed food diary found over two-thirds of participants did not meet BCAA reference intakes (F.4826). It has also been shown that phenylbutyrate therapy depletes plasma BCAAs (F.6123, F.7873). Due to the risk for plasma EAA and BCAA deficiency, one expert opinion recommended assessing protein and energy intake distribution throughout the day as well as considering the quality of the protein consumed (F.4756).

Protein-restricted diets can increase the risk of nutrient deficiencies, including inadequate intake of EAAs, BCAAs, and micronutrients. Some medical foods do not provide all required nutrients (F.7802) and individuals not consuming medical foods may lack essential nutrients in their diet, further highlighting the need for ongoing macro- and micronutrient assessment (F.7802). Regular screening for vitamin and mineral deficiencies is recommended, including monitoring for physical signs such as thin or sparse hair, hair loss, skin rashes, and other indications of protein or micronutrient deficiency (F.6480, F.7963).

Clinical signs of nutrient deficiencies should be assessed using a nutrition-focused physical exam, particularly in cases of suspected protein and amino acid deficiencies. Skin and hair abnormalities, such as brittle hair and acrodermatitis enteropathica-like dermatosis, have been documented in UCDs with deficiencies in arginine and other amino acids (F.5630, F.6226, F.7139). Protein deficiency-related skin rashes have been observed in CPS (F.7139). Additionally, a case series showed trichorrhexis nodosa and alopecia improved following arginine supplementation and dietary adjustments (F.7941).

Delphi 1 Results

There was strong consensus among respondents that dietary intake should be assessed at each routine clinic visit for nutritional adequacy and adherence (100%) and analyzed for nutrient content whenever a blood sample is taken (92%).

Agreement that a nutrition-focused physical exam should be performed at routine clinic visits fell just short of consensus (79%) for mild UCD and reached consensus (83%) for severe UCD.

There was strong agreement (92%) that telemedicine is appropriate to use for routine clinic visits in mild disease, though agreement fell just short of consensus (75%) for those with severe disease.

Delphi 2 Results

Respondents unanimously agreed that telemedicine is appropriate for routine visits in mild and severe UCDs if anthropometrics and labs can be obtained as needed. Several respondents noted that alternating in-person and telehealth visits can balance physical exam requirements with patient convenience and suggested telehealth may be most appropriate for individuals seen more than once annually.

There was strong agreement (96%) for the proposed frequency of nutrition encounters (see Table.283), including those associated with a clinic visit (in-person or telemedicine) as well as interim telephone encounters. Two respondents suggested that interim contacts for children aged 1-8 years should occur at least every three months, and another noted that encounter frequency may be adjusted for stable individuals.

Anthropometric monitoring (weight, height, and head circumference) is essential, as poor growth outcomes, particularly height, have been observed in several studies. A 2016 survey of 65 individuals with UCDs in Japan found that 72% had growth retardation, particularly in OTC, with height below the 10th percentile in 32% of males and 52% of females (F.6650). A 2020 retrospective review of 205 children with UCDs demonstrated that postnatal growth retardation is common and associated with age, disease onset, and their interaction (F.6328). Additionally, a 2014 longitudinal study reviewing 614 individuals with UCDs found that height velocity was lower than expected in UCD (F.6122).

Case studies also highlight the impact of early diagnosis and nutrition intervention on growth. A 1980 case report demonstrated that an increase in protein intake improved growth in CPS (F.7326). A 2022 case series of two ARG siblings linked the individuals' short stature to protein aversion prior to diagnosis, and growth improved after dietary intervention in the older sibling (F.6648). A 2005 case series found that one individual with OTC had a declining head circumference before diagnosis, which improved with treatment, while another individual with OTC remained microcephalic (F.7941).

Additionally, individuals with a UCDs may be prone to higher fat mass. A 2022 study of 18 adults, including 12 with UCDs found that individuals on low protein diets had higher fat mass and fat mass index (assessed by bioimpedance analysis) compared to reference values, particularly those receiving EAA-based medical foods (F.4826). The study emphasized the need for regular assessments of physical activity levels and consideration of fat-free mass to tailor dietary interventions.

Guidelines and expert opinions reinforce the importance of regular anthropometric monitoring. The 2019 European guidelines include tracking growth, head circumference, and clinical signs of protein and vitamin deficiencies (F.7963). A 2001 expert review highlighted anthropometrics as part of routine clinical monitoring (F.4691), and a 2000 review emphasized that inadequate protein intake may be reflected in poor linear growth or low BCAA concentrations (F.4662). While specific intervals for anthropometric assessments are not clearly defined in the literature, they have been described as "frequent", particularly in the first year of life (F.5982), "regular" (F.6373, F.6651), and "routine" as part of ongoing clinical evaluations (F.7963).

Delphi 1 Results

There was strong agreement (91%) that anthropometrics (height and weight) should be assessed at every clinic visit for both individuals with mild and severe disease.

The importance of regular plasma amino acid and ammonia monitoring is well established, though the best marker of metabolic stability in well individuals with UCDs is debated. Plasma ammonia concentrations are a primary biochemical indicator; however, ammonia concentrations fluctuate (F.5618) and are subject to measurement errors from sampling conditions, making glutamine a useful additional marker (F.7763). A 2011 retrospective review of 39 individuals with UCDs (excluding ARG) found a positive correlation between ammonia and glutamine across all subtypes (F.7763). Furthermore, a high proportion of paired laboratory samples showed elevated glutamine despite normal ammonia, especially in OTC, CPS, and late-onset cases, indicating plasma glutamine may be a long-term indicator of metabolic control (F.7763). However, glutamine concentrations correlate more weakly with metabolic crisis risk than ammonia (F.5618) and may be less useful as a biomarker in CIT-I, where normal concentrations can still be associated with significant hyperammonemia (F.5931).

The target ammonia concentration for UCD management varied across sources with 2019 European guidelines including a target of <80 µmol/L for long-term metabolic stability for those outside the neonatal period (F.7963). Some expert opinions recommend stricter goals, with a preferred target of <40 µmol/L (F.4691), while others suggest an upper limit of ≤150 µg/dL (approximately 88 µmol/L) (F.6651). A 2019 clinician survey noted variability in ammonia reporting but found consensus around aiming for <35-50 µmol/L in treatment settings (F.4579).

Target plasma glutamine should generally be maintained <1000 μmol/L to support metabolic stability and reduce the risk of neurotoxicity. Multiple sources, including expert opinions and guidelines, support this threshold as a treatment goal (F.5648, F.4961, F.6651, F.6696, F.7963).

For individuals with ARG, plasma arginine should be kept as low as possible, with targets reported as the upper end of the normal range (<200 µmol/L) (F.7963) to improve outcomes and minimize complications (F.7716), and <300 µmol/L in a patient with one mild mutation (F.5623).

Delphi 1 Results

For mild and severe UCDs, there was consensus to monitor plasma amino acids at every clinic visit (96% and 88%, respectively). In contrast, there was no agreement to measure ammonia at every clinic visit in mild or severe UCDs (58% and 75%, respectively) with some respondents indicating ammonia should be monitored as indicated.

There was strong agreement (92%) to routinely monitor plasma glutamine as the best marker of metabolic stability in UCDs. There was also agreement that a combination of ammonia and elevated glutamine are considered the primary drivers for initiating/escalating nutrition therapy for CPS, OTC, CIT-I, and ASA. For individuals with ARG, respondents were split between ammonia with elevated glutamine or plasma arginine as the primary driver for nutrition therapy. Additionally, one respondent clarified there is no single biochemical marker that drives therapy, noting it is generally a combination of biochemical markers and clinical status.

Delphi 2 Results

Regarding the frequency of ammonia monitoring, respondents agreed (83%) that testing should be performed as indicated in mild UCD. However, there was no consensus on measuring ammonia concentrations at every clinic visit in severe UCD (74%). One respondent noted that, in stable patients with known baseline ammonia concentrations, random checks may be of limited value due to challenges in obtaining reliable samples.

For individuals with ARG, there was consensus (82%) to target plasma arginine concentrations below 200 µmol/L to reduce the risk of neurological complications, although several respondents commented on the difficulty of consistently achieving levels this low.

Large cohort and cross-sectional studies have shown that individuals with UCDs often have reduced or low-normal plasma BCAA concentrations, regardless of protein intake (F.6328), with concentrations negatively correlated with sodium phenylbutyrate use (F.6122, F.6123). Expert opinions recommend monitoring plasma EAAs to evaluate protein adequacy (F.5648), typically every 4-6 months or more often during periods of growth or illness (F.7801). Considering the negative association between phenylbutyrate use and plasma BCAA, routine monitoring for BCAA depletion is also encouraged (F.6122). The 2019 European guidelines emphasize maintaining plasma EAA and BCAA concentrations within the normal range (F.7963).

Historically, serum albumin and prealbumin have been considered as markers of nutritional status. However, authors of a 2021 ASPEN position paper clarify that serum albumin and prealbumin are not valid markers of nutritional status but are instead indicators of inflammation and nutrition risk (L.455). The authors note that declines in visceral proteins during acute or chronic illness result from hepatic reprioritization of protein synthesis, increased capillary permeability, and redistribution into the interstitial space, all driven by the inflammatory response. While these proteins correlate with poor clinical outcomes, they do not reflect total body protein, muscle mass, or dietary intake. Thus, albumin and prealbumin should not be used to diagnose malnutrition or monitor the efficacy of nutrition support, though normalization of these values may signal resolution of inflammation. Rather, it is suggested to integrate inflammatory markers into overall nutrition risk assessment, while relying on validated tools, anthropometrics, and clinical judgment for comprehensive nutritional evaluation (L.455).

Vitamin, mineral, and trace element status should be monitored in individuals with UCDs, as protein-restricted diets may provide inadequate amounts of essential micronutrients. Periodic assessment of vitamins (e.g., 25-OH vitamin D, vitamin B12, methylmalonic acid), minerals (e.g., CBC, ferritin, transferrin), trace elements (e.g., zinc and copper), and essential fatty acids (e.g., red blood cell or plasma fatty acid profile) is warranted to identify and treat deficiencies (F.4691, F.5648, F.7963). However, the optimal frequency of monitoring is not well described.

Case reports and a cross sectional study also suggest individuals with UCDs on low protein diets are also at increased risk for carnitine deficiency (F.4556, F.6060, F.6075, F.6770), and monitoring carnitine status may be beneficial (F.7963).

Correlation with Dietary Intake

Plasma amino acid and ammonia concentrations should be interpreted in the context of dietary intake, amino acid supplementation, and clinical status. Protein and energy intake should be assessed in tandem with plasma amino acids (F.7802), as this helps to evaluate protein tolerance and response to dietary changes (F.7326). One expert opinion suggested amino acids and ammonia should be measured 1-2 weeks after dietary changes, as amino acid concentrations take 2-5 days to equilibrate (F.5648). More frequent monitoring is recommended during periods of illness, stress, or growth (F.7963, F.7801).

The timing of lab measurements is also important for accurate interpretation. Plasma amino acid monitoring within three hours of a meal or EAA-based medical food may reflect recent dietary intake rather than baseline concentrations (F.7111). The European guidelines encourage standardizing blood sampling, ideally 3 to 4 hours post-meal and at the same time of day (F.7963). Based on findings from a 1982 case control study, authors suggest it may be more informative to assess ammonia in CIT-I when measured postprandially rather than fasting due to nocturnal ammonia fluctuations (F.6341).

Delphi 1 Results

Agreement fell just short of consensus that plasma amino acid concentrations provide the most relevant information to assess protein sufficiency (79%). Two respondents commented using growth (in infants and children) or a combination of growth, biochemical results, and clinical assessment to evaluate protein sufficiency, and two others reported using either total protein plus plasma amino acids or prealbumin.

There was unanimous agreement that blood samples for plasma amino acid analysis should be taken at least 2 hours after consuming food/medical food. Most respondents (96%) also agreed individuals should be encouraged not to skip medication (e.g., scavenger) or supplement doses to accommodate a blood draw.

There was no consensus on the frequency of monitoring nutritional laboratory markers (e.g., vitamins, minerals, trace elements, cholesterol/triglycerides, total/free carnitine, essential fatty acid profile, etc.). However, monitoring preferences differed by marker. For micronutrient assessments, including vitamin D and ferritin, most respondents favored routine monitoring annually or even per clinic visit, whereas for other tests, most respondents preferred monitoring as clinically indicated in mild or severe disease.

Delphi 2 Results

There was unanimous agreement to monitor plasma amino acids (including BCAA, EAA, arginine, and citrulline) as the primary biochemical measure to assess protein adequacy in UCDs.

Individuals with UCDs on protein-restricted diets may be at increased risk for osteoporosis (F.7963). Both the 2012 (F.6373) and 2019 European UCD guidelines (F.7963) highlight the need for monitoring bone mineral density, as individuals with UCD may be vulnerable to low bone mineral density and osteoporosis associated with protein restriction. However, published and gray literature provide limited data to define the optimal age to begin screening, the frequency of repeat assessment, or indications for dual-energy x-ray absorptiometry (DXA) screening in individuals with UCDs. Therefore, more specific guidance could not be developed at this time. This recommendation is based primarily on expert consensus and individualized clinical judgment, taking into account factors such as the severity and duration of dietary protein restriction, inadequate calcium or vitamin D intake, poor growth or low body mass, history of fractures, limited weight-bearing activity or reduced mobility, and other clinical concerns for low bone mineral density.

In other IEM managed with long-term intact protein restriction, such as phenylketonuria (PKU), expert groups have suggested obtaining a baseline assessment during adolescence with subsequent follow-up guided by initial results and individual risk factors (L.472). Although comparable data are not available in individuals with UCDs, this may provide a reasonable framework for clinical consideration.

Delphi 1 Results

There was consensus to monitor bone mineral density via a DXA scan as indicated (82%).

It is well established that UCDs can lead to neurodevelopmental impairment, particularly if hyperammonemia is not adequately controlled (F.5271, F.6614, F.7762). A 2003 review of 88 individuals with UCDs found that neither age at symptom onset nor timing of diagnosis reliably predicted developmental outcomes—some individuals with neonatal onset remained cognitively intact, while others with late-onset disease experienced significant delays (F.5271). In OTC specifically, neurocognitive risk in early-onset cases correlated with peak ammonia concentrations, whereas in late-onset cases, it was more closely linked to the number of hyperammonemic episodes (F.6478). Additionally, a 2019 clinician survey highlighted that even modest elevations in ammonia may negatively affect neurocognitive function (F.4579).

In contrast, data specific to ASA suggest that cognitive impairment is common even in individuals diagnosed through newborn screening and managed before significant hyperammonemia occurs. One study found that 4 of 13 individuals with ASA diagnosed via NBS had learning disabilities despite early treatment and mild disease (F.5126). Similarly, 3 of 5 individuals with ASA in a Korean cohort had subnormal developmental scores (F.7170). Neuroimaging findings in ASA, including reduced brain creatine and guanidinoacetate, suggest that brain injury may result from mechanisms other than hyperammonemia (F.7682). These findings highlight the need for routine neurodevelopmental monitoring in ASA, even in the absence of metabolic decompensation.

The range of affected outcomes in UCDs is broad, extending beyond intelligence quotient (IQ) to include executive function, memory, visual processing, motor coordination, and emotional regulation (F.4811, F.5794, F.6478). In ARG, individuals may have learning difficulties, spasticity, and gait abnormalities, even in the absence of severe hyperammonemia (F.4727, F.5290, F.5292, F.6367). Subclinical deficits may also be present, especially among female OTC carriers previously considered asymptomatic (F.4811, F.7963). Structural and functional neuroimaging reveals changes in patients who do not present with overt symptoms (F.4846, F.7682), and modalities such as MRS and fMRI may help identify those at risk for further injury.

Neurodevelopmental testing, including IQ and domain-specific assessments, is typically performed at regular intervals in UCDs, regardless of severity (F.7963). Some centers follow standardized, age-specific protocols, such as evaluations at ages 1, 3, 6, 7, and 9 years (F.6918). Routine or periodic assessments facilitate early identification of learning and/or behavioral concerns (F.6132), allowing for timely referral and intervention.

Health-related quality of life (HRQoL), anxiety, stress, and psychosocial factors are also important patient outcomes (F.7963). Studies show that the burden of disease, including dietary restriction, metabolic instability, and hospitalization, significantly impacts the well-being of both individuals with UCDs and their families (F.4579, F.4598, F.4952). HRQoL may be lower in individuals with UCDs compared to healthy peers, and caregivers often report lower HRQoL than those with UCD (F.4598). Psychological monitoring support should be considered an essential component of care (F.7963).

Delphi 1 Results

There was strong agreement (87%) that all children with a UCD, regardless of disease severity, should undergo developmental assessment and formal cognitive testing.

There was also strong consensus (96%) to screen individuals with UCDs for anxiety and depression at least annually.