1H MRS identifies symptomatic and asymptomatic subjects with partial ornithine transcarbamylase deficiency

A L Gropman, S T Fricke, R R Seltzer, A Hailu, A Adeyemo, A Sawyer, J van Meter, W D Gaillard, R McCarter, M Tuchman, M Batshaw, Urea Cycle Disorders Consortium, Mark L Batshaw, Mendel Tuchman, Uta Lichter-Konecki, Robert McCarter, Andrea L Gropman, Stanley Fricke, John Van Meter, Rebecca Seltzer, Brendan Lee, Marshall Summar, Brendan Lanpher, Marc Yudkoff, Stephen Cederbaum, George Diaz, Douglas Kerr, Shawn McCandless, Arthur Zinn, Margretta Seashore, Jeffrey Krischer, Hye Seung Lee, Rachel Richesson, Mary Lou Oster-Granite, Elaine Collier, Giovanna Spinella, Cynthia LeMons, A L Gropman, S T Fricke, R R Seltzer, A Hailu, A Adeyemo, A Sawyer, J van Meter, W D Gaillard, R McCarter, M Tuchman, M Batshaw, Urea Cycle Disorders Consortium, Mark L Batshaw, Mendel Tuchman, Uta Lichter-Konecki, Robert McCarter, Andrea L Gropman, Stanley Fricke, John Van Meter, Rebecca Seltzer, Brendan Lee, Marshall Summar, Brendan Lanpher, Marc Yudkoff, Stephen Cederbaum, George Diaz, Douglas Kerr, Shawn McCandless, Arthur Zinn, Margretta Seashore, Jeffrey Krischer, Hye Seung Lee, Rachel Richesson, Mary Lou Oster-Granite, Elaine Collier, Giovanna Spinella, Cynthia LeMons

Abstract

Objective: To evaluate brain metabolism in subjects with partial ornithine transcarbamylase deficiency (OTCD) utilizing (1)H MRS.

Methods: Single-voxel (1)H MRS was performed on 25 medically-stable adults with partial OTCD, and 22 similarly aged controls. Metabolite concentrations from frontal and parietal white matter (FWM, PWM), frontal gray matter (FGM), posterior cingulate gray matter (PCGM), and thalamus (tha) were compared with controls and IQ, plasma ammonia, glutamine, and disease severity.

Results: Cases ranged from 19 to 59 years; average 34 years; controls ranged from 18 to 59 years; average 33 years. IQ scores were lower in cases (full scale 111 vs. 126; performance IQ 106 vs. 117). Decreased myoinositol (mI) in FWM (p=0.005), PWM (p<0.001), PCGM (p=0.003), and tha (p=0.004), identified subjects with OTCD, including asymptomatic heterozygotes. Glutamine (gln) was increased in FWM (p<0.001), PWM (p<0.001), FGM (p=0.002), and PCGM (p=0.001). Disease severity was inversely correlated with [mI] in PWM (r=-0.403; p=0.046) and directly correlated with [gln] in PCGM (r=0.548; p=0.005). N-Acetylaspartate (NAA) was elevated in PWM (p=0.002); choline was decreased in FWM (p=0.001) and tha (p=0.002). There was an inverse relationship between [mI] and [gln] in cases only. Total buffering capacity (measured by [mI/mI+gln] ratio, a measure of total osmolar capacity) was inversely correlated with disease severity in FWM (r=-0.479; p=0.018), PWM (r=-0.458; p=0.021), PCGM (r=-0.567; p=0.003), and tha (r=-0.345; p=0.037).

Conclusion: Brain metabolism is impaired in partial OTCD. Depletion of mI and total buffering capacity are inversely correlated with disease severity, and serve as biomarkers.

Conflict of interest statement

Disclosures: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Depiction of voxel locations from which metabolism was sampled: a) PWM= parietal white matter ; b) PCGM= posterior cingulate gray matter; c) tha= thalamus; d) FWM= frontal white matter; e) FGM= frontal gray matter.
Figure 2
Figure 2
a–e: These bar graphs demonstrate the concentrations of the major measured metabolites in brain in subjects and controls. Regions of significance between subjects carrying a mutation in the OTCD gene and controls is shown as a P value
Figure 3
Figure 3
a–c: Disease severity and metabolite trends for several brain regions studied
Figure 4
Figure 4
Correlations between plasma and brain glutamine levels
Figure 5
Figure 5
This figure shows the inverse relationship between brain gln and mI in subjects with OTCD but not controls, implicating impaired osmoregulation.
Figure 6
Figure 6
Osmotic index is indicated by ratio of mI divided by total osmolytes (gln + mI).
Figure 7
Figure 7
This overlapping spectrum obtained from the parietal white matter in a subject and age matched control illustrates differences in the concentration of several key metabolites.

Source: PubMed

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