Consistent with previous research, our results suggest that children presenting with neonatal onset UCDs have poorer outcome than those who present later in childhood. With regard to basic intelligence, approximately half of the NO group was in the range of intellectual disability, including a substantial number (approximately 30%) who were severely impaired. In comparison, only about a quarter of the LO group was in the range of intellectual disability with only a very small number (< 5%) with moderate to severe disability. However, it is important to note that although there are fewer children with severe intellectual disability in this group, only 65% of the late onset group showed IQ scores in the “average” range (as compared to 19% in the neonatal onset group). Thus, although the LO group is performing much better than the NO group as whole, a substantial number are functioning below age expectations. Similar results were obtained for adaptive skills in that children with NO had greater impairments in comparison to children with LO disease. Across both groups, adaptive skills were generally commensurate with the intellectual abilities. In addition, there is some preliminary evidence from the questionnaire data and our clinical experience that even children with average intellectual abilities have indications of other neuropsychological deficits, which will be quantitatively summarized in future papers. This is consistent with the finding that the children in our group have a higher number of previously reported diagnoses of learning disabilities and ADHD.
Although the discrepancy between the NO and LO groups in this study is similar to those identified in previous studies, the overall level of disability across both groups is notably lower than has been reported previously. In studies of individuals with NO disease, the percentage with any level of ID was as high as 60–80% in prior studies (4
), as opposed to the 50% noted in this study. Similarly, previous research has suggested a higher proportion of disability in children with partial UCDs. We previously reported that >50% of school age subjects with partial UCDs were in the range of intellectual disability (5
The relatively lower rates of intellectual impairment in this study may be attributable to several factors. First, the overall sample size in this study is substantially larger than the sample sizes in previous studies, which generally reported on less than 25 patients. Additionally, it is possible that there have been improvements in functional outcome as a result of improved screening, recognition, and treatment protocols. Finally, much of the previous work has only examined individuals with severe forms of the disease, while this study includes a wider range, many with milder disease presentations. For example, almost one third of the overall subjects were females with OTC, who are known to typically have a milder form of the disease. Although there were not significant differences noted on any of the summary measures of intelligence, adaptive functioning, or behavioral/emotional functioning between the females and males with OTC, the percentage of males with intellectual disabilities was substantially higher overall (33% vs. 13%) when the lowest functioning (“untestable”) individuals are included in the numbers.
Closer examination of the three most prevalent diagnoses (OTC, AL and AS deficiencies), found the overall rates of intellectual disability to be variable. The OTC group had the lowest percentage of individuals with intellectual disabilities (20%), which is consistent with the low numbers of individuals in our OTC group with NO disease (~8%). In contrast, both the AL and AS Deficiency groups had a moderate percentage of subjects (40 to 50%) with intellectual disabilities, which is consistent with a higher percentage of individuals in these groups with NO disease. Interestingly, the AL and AS groups had equal or lower percentages of individuals with a history of at least 1 hyperammonemic episode (67% in AD deficiency group, 40% in the AL group vs. 64% in the OTC group). This finding is consistent with previous papers that have suggested that there may be additional mechanisms contributing to the cognitive dysfunction in individuals with the distal defects (17
), such as argununosuccinic aciduria or citrulline. It is also interesting to note that although the overall rates for any level of intellectual disability were similar in the AS and AL deficiency groups, the AS group had several individuals with more severe intellectual disabilities. Upon closer examination, the AS deficiency group had a greater percentage of individuals with NO and with a history of at least 1 previous hyperammonemic episode. Again, it may be possible that cognitive dysfunction in these individuals is related to a combination of factors, not just hyperammonemia.
Results of our analysis for children under age 3 yielded somewhat different results than the preschool and school age sample. Specifically, 8% of the NO group and none of the LO onset group presented with significant cognitive delay, which is much lower than the percentage of preschool and school age children with intellectual deficits. In addition, there were no significant differences between the groups in either developmental or adaptive functioning. However, the composite scores for both groups were between ½ to 1 standard deviation below the normative mean in all areas, including cognitive development, language, motor skills, and adaptive functioning. Finally, there was an affect on IQ for having a history hyperammonemia. Overall, these results suggests that although most of the young children with UCD do not present with severe impairments, there is evidence that their development is not entirely normal and that there is some impact of hyperammonemia, even if it does not present in the neonatal period.
There may be several reasons why fewer children are presenting with cognitive impairments in the youngest age group. One possibility is related to the sensitivity of the testing. The majority of the children in this group were tested at either age 6 months or 18 months of age. The range of behaviors that can be measured are more limited in early infancy, particularly before age 1. In addition, previous research has demonstrated poor predictability of the Bayley Scales of Infant Development (Second Edition) for cognitive ability at school age, both in medically at risk and normal populations (25–27). However, it has also been noted that although the predictive ability of the Bayley is somewhat poor, it is better in children with “neurosensory impairments”. Thus, poor performance on the Bayley in children with UCDs who have significant neurological impairments may indeed be a predictor of future cognitive difficulties in childhood.
A second possibility is that over time, children with UCD may demonstrate stagnation, slowed development, or even a decline in abilities related to their disease process, particularly if characterized by recurrent episodes of hyperammonemia. This would be consistent with previous studies (9
), which demonstrated decline in cognitive scores over time in a group of females with OTC. Although we do not yet have enough longitudinal data to answer this question, we evaluated the mean scores across several age ranges to identify evidence supporting this hypothesis. There was some evidence suggesting that overall cognitive/intellectual scores in the cross-sectional analyses of children in the 0–3, 3–5 and 6–16 age bands decline over time, particularly in the neonatal onset group (i.e., Cognitive Composite= 86 for 0–3, FSIQ=78 for ages 3–5 and 71 for ages 6–16). This does not necessarily suggest that children with UCD are losing skills, but that their developmental trajectory is slower than that of the normal population.
Although significant differences were observed for intelligence and adaptive skills between the two age of onset groups, no differences were noted on parent report of behavioral, emotional and executive functioning. There was no evidence of clinically significant behavioral or emotional problems in the group as a whole. However, compared to normative data, there is a slightly greater proportion of children with UCDs who have behavioral and emotional difficulties, though the majority have only mild problems (16–17% with mild difficulties and 4% with clinically significant symptoms). This included both internalizing (e.g., anxiety, depression, withdrawal) and externalizing (e.g., aggression, conduct issues) symptoms. These results are consistent with a recent meta-analysis of psychosocial problems in children with chronic illnesses, which suggested that these children are at a slightly elevated risk of psychosocial distress, although only a minority experience clinical symptomatology (28
). In addition, the children in this cohort show other behavioral/emotional strengths, including a minimal percentage with previous diagnoses of Autism spectrum disorders, mood disorders, and other psychiatric disorders.
There is even greater evidence to suggest that individuals with UCD have difficulties with several aspects of attention and executive functioning. Executive functioning refers to a set of skills important for goal directed behavior and includes skills in cognitive, behavioral, and emotional arenas. In comparison to the normative population, our sample of children with UCDs was reported to have problems with attention and select metacognitive skills. This included their ability to sustain working memory, plan and organize their approach to tasks, and monitor their mistakes. These findings are consistent with previous papers, which noted executive functioning weaknesses in a group of adult females who were heterozygous carriers of the OTC gene (11
). These results support the notion that there is selective vulnerability of white matter in individuals with UCD that is associated with hyperammonemia and is also consistent with neuroimaging studies (12
). It will be critical to more closely examine the pattern of neuropsychological strengths and weaknesses in this population beyond measures of overall intelligence and development.
In summary, children with UCDs present with a wide variety of cognitive outcomes. Children with neonatal onset disease have a much higher likelihood of having an intellectual disability, which becomes even more evident with increasing age. However, even children with late onset and presumably more mild disease presentation demonstrate evidence of neurocognitive and behavioral difficulties, particularly in aspects of executive functioning. A goal of future analyses will be to examine the broader neuropsychological profile of this population and identify factors that may predict their outcome. Finally, we also plan to further examine different disease subtypes and the relationship between proximal vs. distal enzyme defects and neuropsychological functioning.