Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database

Abstract

Background: Ornithine transcarbamylase deficiency (OTCD) due to an X-linked OTC mutation, is responsible for moderate to severe hyperammonemia (HA) with substantial morbidity and mortality. About 80% of females with OTCD remain apparently "asymptomatic" with limited studies of their clinical characteristics and long-term health vulnerabilities. Multimodal neuroimaging studies and executive function testing have shown that asymptomatic females exhibit limitations when stressed to perform at higher cognitive load and had reduced activation of the prefrontal cortex. This retrospective study aims to improve understanding of factors that might predict development of defined complications and serious illness in apparent asymptomatic females. A proband and her daughter are presented to highlight the utility of multimodal neuroimaging studies and to underscore that asymptomatic females with OTCD are not always asymptomatic.

Methods: We review data from 302 heterozygote females with OTCD enrolled in the Urea Cycle Disorders Consortium (UCDC) longitudinal natural history database. We apply multiple neuroimaging modalities in the workup of a proband and her daughter.

Results: Among the females in the database, 143 were noted as symptomatic at baseline (Sym). We focused on females who were asymptomatic (Asx, n = 111) and those who were asymptomatic initially upon enrollment in study but who later became symptomatic sometime during follow-up (Asx/Sym, n = 22). The majority of Asx (86%) and Asx/Sym (75%) subjects did not restrict protein at baseline, and ~38% of Asx and 33% of Asx/Sym subjects suffered from mild to severe neuropsychiatric conditions such as mood disorder and sleep problems. The risk of mild to severe HA sometime later in life for the Asx and Asx/Sym subjects as a combined group was ~4% (5/133), with ammonia ranging from 77 to 470 μM and at least half (2/4) of subjects requiring hospital admission and nitrogen scavenger therapy. For this combined group, the median age of first HA crisis was 50 years, whereas the median age of first symptom which included neuropsychiatric and/or behavioral symptoms was 17 years. The multimodal neuroimaging studies in female heterozygotes with OTCD also underscore that asymptomatic female heterozygotes with OTCD (e.g., proband) are not always asymptomatic.

Conclusions: Analysis of Asx and Asx/Sym females with OTCD in this study suggests that future evidence-based management guidelines and/or a clinical risk score calculator for this cohort could be useful management tools to reduce morbidity and improve long-term quality of life.

Keywords: Urea Cycle Disorders Consortium; diffusion tensor imaging; functional MRI; functional near‐infrared spectroscopy; hyperammonemia; magnetic resonance spectroscopy; ornithine transcarbamylase deficiency; prefrontal cortex; urea cycle disorder.

FIGURE 1

Neuroimaging phenotype in proband and other female carriers with OTCD. (a) fNIRS: fNIRS after a Stroop task in age‐matched normal female controls (1) versus heterozygote females with OTCD (2) from Figure 6 of Anderson et al. (2020). (b) Structural MRI: Nonspecific white matter intensities (white arrows) found in both Asx and Sym female heterozygotes with OTCD on FLAIR imaging. This imaging modality does not offer specificity for this disorder; (c) fMRI: Normal female control showing frontal activation (green, bottom images) on a Stroop task, which is left side dominant, while the proband heterozygote with OTCD (red, top images) showing bilateral activation as well as recruitment of other regions; (d) DTI: Diffusion tensor imaging; and (e) ¹H MRS: Age‐matched normal control (green line), Asx female (blue line), and Sym female (red line). Choline (chol; blue arrow) levels are reduced in both the Sym and Asx female heterozygotes with OTCD, reflecting loss of membrane integrity. Interestingly, myoinositol (mI; yellow arrow) shows normal high levels in a normal control and low level in a Sym female heterozygote with OTCD. Asx female heterozygote with OTCD showing intermediate, but lower mI levels than normal control female (see Table 6). Asx, asymptomatic; Sym, symptomatic.

FIGURE 2

Kaplan Meier curves with right censored data of (a) age at first hyperammonemia and (b) age at first symptom, of the asymptomatic at any time (Asx) and asymptomatic at baseline who became symptomatic later while in the study (Asx/Sym) cohorts together.