Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency

Abstract

Background Urea cycle disorders are caused by dysfunction in any of the six enzymes and two transport proteins involved in urea biosynthesis. Our study focuses on Ornithine Transcarbamylase deficiency (OTCD), an X-linked disorder that results in a dysfunctional mitochondrial enzyme, which prevents the synthesis of citrulline from carbamoyl phosphate and ornithine. This enzyme deficiency can lead to hyperammonemic episodes and severe cerebral edema. The objective of this study was to use a cognitive battery to expose the cognitive deficits in asymptomatic carriers of OTCD. Materials and Methods In total, 81 participants were recruited as part of a larger urea cycle disorder imaging consortium study. There were 25 symptomatic participants (18 female, 7 male, 25.6 years ± 12.72 years), 20 asymptomatic participants (20 female, 0 male, 37.6 years ± 15.19 years), and 36 healthy control participants (21 female, 15 male, 29.8 years ± 13.39 years). All participants gave informed consent to participate and were then given neurocognitive batteries with standard scores and T scores recorded. Results When stratified by symptomatic participant, asymptomatic carrier, and control, the results showed significant differences in measures of executive function (e.g. CTMT and Stroop) and motor ability (Purdue Assembly) between all groups tested. Simple attention, academic measures, language and non-verbal motor abilities showed no significant differences between asymptomatic carriers and control participants, however, there were significant differences between symptomatic and control participant performance in these measures. Conclusions In our study, asymptomatic carriers of OTCD showed no significant differences in cognitive function compared to control participants until they were cognitively challenged with fine motor tasks, measures of executive function, and measures of cognitive flexibility. This suggests that cognitive dysfunction is best measurable in asymptomatic carriers after they are cognitively challenged.

Improving long term outcomes in urea cycle disorders‐report from the Urea Cycle Disorders Consortium

“…These biomarkers correlated with neuropsychological test results, suggesting that perturbations in brain metabolites impact functioning, even when the individual experiences no clinical symptoms associated with OTCD. As a result, subclinical injury may go unrecognized and untreated because routine clinical assessments underestimate the degree of injury (Sprouse et al, 2014). This finding was consistent with our previously published neurocognitive studies (Krivitzky, et al, 2009).…”

“…As noted in Figure 5, individuals with OTCD performed less well on the Comprehensive Trail Making Test. Processing speed and selective attention also appeared to be affected, especially with higher cognitive loading, as indicated by poorer performance on the Color Stroop task (Figure 6) (Sprouse, et al, 2014). …”

Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency

“…Some of the “asymptomatic” OTCD carriers have mild symptoms, while others show no symptoms yet have MRS findings of elevated glutamine and low myoinositol [50], as well as some cognitive deficits [48]. Therefore, we feel that this scale does not accurately reflect the subtle differences that exist within OTCD patients with regards to symptom severity and cognitive functioning.…”

Impairment of cognitive function in ornithine transcarbamylase deficiency is global rather than domain‐specific and is associated with disease onset, sex, maximum ammonium, and number of hyperammonemic events

“…Overall, EO patients have poorer intellectual and behavioral outcomes than LO patients, and specific deficits in measures of executive functions, cognitive flexibility and speed, and fine motor dexterity despite intellectual abilities within the average range have been reported in asymptomatic female carriers . Selective vulnerability of white matter but better preservation of grey matter has been suggested as an explanation …”

“…27,28 Selective vulnerability of white matter but better preservation of grey matter has been suggested as an explanation. 25,29 The aim of the present study is to investigate the associations between timing of disease onset type (EO, LO, and asymptomatic), degree and frequency of hyperammonemia, sex of the individual, and number of clinical findings with results on tests of cognitive functioning in five domains (global intelligence, executive functions, memory, visual-motor integration, and visual perception). The primary question is whether the effect of OTCD on cognitive functioning is global or specific, that is, whether selected cognitive domains will be affected differently.…”