Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders

Abstract

Objective: Individuals with urea cycle disorders (UCDs) often present with intellectual and developmental disabilities. The major aim of this study was to evaluate the impact of diagnostic and therapeutic interventions on cognitive outcomes in UCDs.

Methods: This prospective, observational, multicenter study includes data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow-up of 702 patient-years.

Results: The mean cognitive standard deviation score (cSDS) was lower in symptomatic than in asymptomatic (p < 0.001, t test) individuals with UCDs. Intellectual disability (intellectual quotient < 70, cSDS < -2.0) was associated with the respective subtype of UCD and early disease onset, whereas height of the initial peak plasma ammonium concentration was inversely associated with neurocognitive outcomes in mitochondrial (proximal) rather than cytosolic (distal) UCDs. In ornithine transcarbamylase and argininosuccinate synthetase 1 deficiencies, we did not find evidence that monoscavenger therapy with sodium or glycerol phenylbutyrate was superior to sodium benzoate in providing cognitive protection. Early liver transplantation appears to be beneficial for UCDs. It is noteworthy that individuals with argininosuccinate synthetase 1 and argininosuccinate lyase deficiencies identified by newborn screening had better neurocognitive outcomes than those diagnosed after the manifestation of first symptoms.

Interpretation: Cognitive function is related to interventional and non-interventional variables. Early detection by newborn screening and early liver transplantation appear to offer greater cognitive protection, but none of the currently used nitrogen scavengers was superior with regard to long-term neurocognitive outcome. Further confirmation could determine these variables as important clinical indicators of neuroprotection for individuals with UCDs. ANN NEUROL 2019.

Figure 1:. Model-based recursive partitioning for 209 symptomatic UCD individuals.

Cognitive SDS from 138 symptomatic individuals in group 2 (NAGS-D: n=2, CPS1-D: n=2, mOTC-D: n=45, fOTC-D: n=84, HHH-S: n=4, Citrin deficiency: n=1) was associated inversely with the height of initial NH₄⁺_max (β=−0.0012, p=0.006). The association was unchanged if individuals with fOTC-D were excluded from the analysis. UCD individuals belonging to group 1 have lower cSDS than individuals from group 2 (p<0.001, t-test). Gray lines are fitted cSDS from the linear model; the gray shaded area corresponds to 95% confidence interval (CI).

Figure 2:. Height of initial NH₄⁺_max is associated with group affiliation in 240 symptomatic UCD individuals.

The left column (Fig 2A, 2B, and 2C) includes individuals from group 1; the right column (Fig 2D, 2E, and 2F) includes individuals from group 2. The first line (Fig 2A, and 2D) includes individuals with normal cSDS (IQ ≥ 85; cSDS ≥ −1.0), the second line (Fig 2B, and 2E) individuals with low normal to borderline cSDS (70 ≤ IQ < 85; −2.0 ≤ cSDS < −1.0), and the third line (Fig 2C, and 2F) includes individuals with intellectual disability (IQ < 70; cSDS < −2.0). Individuals from group 1 (ASS1-, ASL-, and ARG1-D) suffer more likely from intellectual disability (p<0.001, cumulative link model). Since interaction between initial NH₄⁺_max and group affiliation is significant (p=0.018, cumulative link model) with regard to cognitive outcome, height of initial NH₄⁺_max is associated with impaired neurocognition in group 2 (NAGS-D, CPS1-D, mOTC-D, fOTC-D, HHH-S, and citrin-deficiency) rather than group 1, despite higher initial NH₄⁺_max in group 1 (p<0.001, t-test). Gray lines are fitted probabilities to be assigned to a specific group (normal cSDS, low normal to borderline cSDS or intellectual disability) predicted by the cumulative link model; the gray shaded area corresponds to 95% CI.

Figure 3:. Boxplots reflecting the beneficial cognitive effect of NBS for individuals with ASS1-D (n=49) and ASL-D (n=56).

Descriptive characteristics are presented separately in Table 1. Data are shown as median (black line) and mean (triangle), length of the box corresponds to interquartile range (IQR), upper and lower whiskers correspond to max. 1.5 x IQR, each point represents an outlier. NBS, newborn screening; SX, selective metabolic investigation after the onset of symptoms.

Figure 4:. Modelling the effect of early diagnosis by NBS for age-matched preschool children with ASS1-D (n=21) and ASL-D (n=27).

Descriptive characteristics are presented separately in Table 1. NBS improves cognitive outcome for ASS1-D (p<0.001, ANOVA post-hoc comparison) and ASL-D individuals (p=0.021, ANOVA post-hoc comparison). Gray lines are fitted cSDS values from the linear model; the gray shaded area corresponds to 95% CI. NBS, newborn screening. SX, selective metabolic investigation after the onset of symptoms.

Figure 5:. Mosaic plot presenting the association of disease severity with therapy intensity from 359 UCD individuals at last psychological testing.

Individuals with information on the variables disease onset, cSDS tests, initial NH₄⁺_max, and specific therapy are presented. Individuals belonging to escalation level (EL) 0 (n=50) receive no therapy, whereas individuals on EL 1 (n=96) receive a natural protein intake below 100% WHO safe values (NPI) or L-arginine/-citrulline/-ornithine ± carglumic acid for NAGS-D. EL 2 (n=29) corresponds to NPI and L-arginine/-citrulline/-ornithine ± carglumic acid for NAGS-D. EL 3 (n=147) applies to individuals receiving one scavenger (BZA or PBA) ± NPI ± L-arginine/-citrulline/-ornithine ± carglumic acid for NAGS-D, and EL 4 (n=37) includes individuals receiving two scavengers (BZA and PBA) ± NPI ± L-arginine/-citrulline/-ornithine ± carglumic acid for NAGS-D. The height of the boxes represent the proportion of EL, the widths of the boxes in a row represent the proportions of individuals with a specific disease onset (EO, LO, ASx) within that EL. The intensities of color reflect the discrepancies between observed and expected frequencies. Blue color shows that observed frequencies are higher than expected, red color shows that observed frequencies are lower than expected. Pearson residuals indicate that ASx individuals are overrepresented in EL 0 and 1 and underrepresented in EL 2 to 4. Symptomatic UCD individuals (EO, LO) are similarly distributed within EL 2 to 4. However, (severe) metabolic decompensations increase continuously between EL 2 to 4, as mirrored by the median initial NH₄⁺_max (EL 2: median initial NH₄⁺_max 198.0 μmol/l, n=14/29; EL 3: median initial NH₄⁺_max 270.0 μmol/l, n=111/147; EL 4: median initial NH₄⁺_max 335.5 μmol/l, n=26/37).

Figure 6:. Boxplots reflecting the effects of long-term monoscavenger therapy on cognition of individuals with OTC-D (n=77) and EO ASS1-D (n=21).

77 OTC-D individuals (EO-PBA: n=10; EO-BZA: n=3; LO-PBA: n=52; LO-BZA: n=12) and 21 EO ASS1-D individuals receiving all monoscavenger therapy (EO-PBA: n=17; EO-BZA: n=4) were analyzed with regard to their cognitive outcome. Monoscavenger treatment with PBA is not superior to BZA neither for age-matched EO or LO OTC-D (p=0.41, ANOVA) nor for age-matched EO ASS1-D individuals (p=0.531, t-test). For OTC-D and EO ASS1-D individuals below the weight of 20 kg with sufficient scavenger dose information, both median sodium-phenylbutyrate and median sodium benzoate doses were within the recommended ranges. Data are shown as median (black line) and mean (triangle), length of the box corresponds to interquartile range (IQR), upper and lower whiskers correspond to max. 1.5 x IQR, each point represents an outlier. PBA, sodium/glycerol phenylbutyrate; BZA, sodium benzoate.

Figure 7:. Cognitive SDS of psychological testing after liver transplantation by age at transplantation (months) and disease onset (EO vs. LO).

Individuals with EO (n=40) perform worse than those with LO (n=5; p=0.026, ANOVA). If indication for LTx is made, timely liver transplantation tends to be associated with improved neurocognitive outcome (p=0.087, ANOVA). The interaction between disease onset and age at transplantation is not significant (p=0.76, ANOVA). Gray lines are fitted cSDS values from the linear model; the gray shaded area corresponds to 95% CI.