Medically treated UCD patients require lifelong monitoring including anthropometric data, biochemical tests, dietary and drug review, history of intercurrent illnesses and use of the emergency regimen. Visit intervals should be individualised on the basis of age, growth, severity, metabolic stability and compliance with diet and drug therapy. Young and severely affected patients may need monitoring every 3 months, whilst annual reviews may be enough for older or less affected patients.
Clinical monitoring should address: growth and head circumference, inspection for thin sparse hair, hair loss, skin rashes and other signs of protein/vitamin deficiency, neurological examination and neurocognitive development, liver size and structure (by ultrasound scan). Regular dietary assessments are also essential, either by recall, or when nutritional or compliance problems are suspected, by recording quantitatively diet, supplements and drugs taken in the 3–5 days preceding the visit. The diet needs to be adjusted for age and growth (see below)
[17, 47, 106]. Since low protein diets may increase the risk of osteoporosis, bone density monitoring from time to time may be advisable
Statement #37. Grade of recommendation: D
Clinical, biochemical and nutritional monitoring are essential and should follow an individualised plan.
Laboratory monitoring must include plasma ammonia determination in venous samples (target level <80 μmol/L
[16, 100]). Spurious elevations can be due to poor sample processing, tourniquet, crying, struggling or convulsions
. Sequential determination of ammonia for 24 h, including preprandial, postprandial and fasting samples, is carried out in some centers but its value is uncertain. A reflectometric device (Ammonia Checker™ II)
 exists that allows bedside approximate assessment of ammonia in 3 min using 20 μl of venous blood (but upper limit of detection of this device is 280 μmol/L). It is not recommended for home use since capillary samples are unsuitable because cell contents and sweat contamination can lead to false high values.
The plasma amino acid profile should be determined to ensure that enough arginine/citrulline and EAAs/BCAAs are supplied. Arginine should be in the high normal range and EAAs and BCAAs in the normal ranges. Rising glutamine may indicate impending hyperammonemia. Arbitrarily, glutamine levels are considered tolerable when they do not exceed 1000 μmol/L
[16, 73, 100, 168]. Since glutamine levels change with the fasting/feeding status, being highest after the overnight fast
, sampling should be standardised, ideally 3–4 h after the last meal
[170, 171]. It is important to consider growth rate, age, actual protein intake and frequency of use of the emergency regimen when interpreting plasma amino acids as low EAA levels do not always necessitate an increase in protein. Decreasing the nitrogen scavenger dose may also help to increase BCAAs concentrations.
Other blood assays can include determination of vitamins (including cobalamin), minerals, trace elements, carnitine, ferritin, cholesterol and triglycerides in plasma and of EFAs in red blood cells and plasma. Blood urea levels are of little value since they depend mainly on arginine intake and tubular urine flow rate. Blood sodium benzoate and/or sodium PBA/phenylacetate assays may be helpful to prevent toxicity in patients receiving high dosages or repeated boluses
Urine determinations : ketone bodies (done at home after instruction of parents) might indicate a catabolic situation. Hippurate quantitation allows assessing compliance with benzoate treatment. Amino acid profiling is not recommended; the value of measuring orotate and orotidine excretion is dubious, although increasing orotate excretion should reflect greater ammonia load and carbamoylphosphate accumulation.
Statement #38. Grade of recommendation: D
Venous ammonia and amino acid levels should be monitored, aiming at levels of ammonia <80 μmol/L, glutamine <1000 μmol/L, arginine in the high normal range and EAAs and BCAAs in the normal range. Rapid reflectometric ammonia assay in venous blood is useful, provided it’s limitations are known by the user.
Neuroimaging should assess possible neuroanatomical alterations, providing "information about the timing, extent, reversibility and possible mechanism of neural injury .... and can be used as an adjunctive measure to predict clinical and neurocognitive outcome”. Magnetic resonance imaging (MRI) should ideally be performed systematically between days 1 and 4 of each coma or stroke-like episode, to follow the changes in the apparent diffusion coefficient (ADC). If general anesthesia is not needed, it should be repeated at approximately 2 year-intervals to allow correlation of motor/language/cognitive development with anatomic changes. MRI sequences should include diffusion tensor imaging, axial T2 and FLAIR, sagittal and axial T1, and magnetic resonance spectroscopy (MRS)
[173–175]. In acute presentations, diffuse cerebral edema is seen as areas of cortex and the underlying white matter presenting abnormal signal intensity, infarct-like aspect and restricted diffusion. These areas are often multiple in one or both hemispheres and are asymmetrical
[176, 177]. Basal ganglia involvement is revealed on T2-weighted images by high intensity signals in the caudate nucleus, putamen, and/or globus pallidus. The deep sulci of the insular and perirolandic regions may also display T1 shortening
. MRS can reveal highly elevated brain glutamine levels
[178, 179]. These elevations are helpful to detect subtle changes in OTC females
[174, 175]. The thalamus, brainstem, the occipital region and the cerebellum tend to be relatively spared and a few months after acute hyperammonemia a very moderate residual hypersignal on the insula and rolandic region may be observed
[13, 176]. Chronic hyperammonemia may convey defective myelination and progressive cerebral atrophy, with nonspecific punctate white matter hyperintensities seen in some patients
Statement #39. Grade of recommendation: D.
To help predict clinical and neurocognitive outcome it appears desirable to perform magnetic resonance imaging early on in each coma or stroke-like episode, and at 2-year intervals. Investigations should include diffusion tensor imaging, axial T2 and FLAIR, sagittal and axial T1 and magnetic resonance spectroscopy.
Cognitive outcomes and psychosocial issues in UCDs
Cognitive outcome appears to be poor for neonatal onset patients, and less so for late-onset patients. Thus, a study with 26 survivors of neonatal hyperammonemic coma found that ~79% were mentally retarded and that the mean IQ value for the entire cohort was only 43
, whereas another study found that ~50% of 33 neonatal patients but only ~25% of 59 late-onset patients presented moderate to severe intellectual disability
. The level and duration of hyperammonemia appear key determinants of the outcome
. It was reported
 that no UCD patient having had >300 μmol/L initial or >480 μmol/L peak plasma ammonia exhibited normal psychomotor development. Nevertheless, another study
 found average or above average IQ values in 33%, 40% or 66% of the ASSD, ASLD and OTCD patients studied, respectively, although the predominance of late-onset OTCD presentations (81%) in that study might account for the good outcome of these patients
. The importance of assessing not only IQ and development but also the specific patterns of neuropsychological strengths and weaknesses was illustrated by the finding in late-onset OTCD patients having normal IQ of deficits of motor planning and execution
 and a specific neurocognitive pattern that included weakness in fine motor dexterity/speed and a trend towards weakness in non-verbal intelligence, visual memory, attention/executive skills and mathematics, although verbal intelligence, memory, learning and reading were strong
. In any case, clinically asymptomatic OTC heterozygotes outperformed symptomatic heterozygotes and the performance improved with higher levels of residual urea synthesis activity, assessed by stable isotope studies, whereas neither the allopurinol test results nor the mutation type correlated with neuropsychological performance in these patients
Statement #40. Grade of recommendation: D
Neonatal onset and prolonged hyperammonemic coma predict severe impairment of future neurocognitive performance. Patients with milder disease or heterozygous carriers for OTCD may develop specific weaknesses in several executive functions even if the IQ is normal. Regular testing for IQ, development and specific abilities/weaknesses is recommended.
As is the general case for parents of chronically ill children
, UCD patients/families can have low health-related quality of life (HrQuOL), with disease-imposed stresses perhaps amplified by delays in diagnosis and treatment resulting from poor general awareness of these diseases
. Thus, the recommendation for chronically ill patients and their families
[184–186] of routine monitoring of emotional, behavioral and psychosocial parameters also applies to UCD patients, aiming at identifying and preventing psychosocial maladjustment
. Psychologists should be involved in patient care early after diagnosis to cope with initial anxiety and with later-developing psychological problems
 and also to assess the cognitive level and neuropsychological functions of the patient.
Statement #41. Grade of recommendation: D
Health-related quality of life, anxiety, stress and psychosocial factors are important outcome parameters. Psychological management is an important component of the care of UCD patients and their families.