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

Abstract

Objective To evaluate brain metabolism in subjects with partial ornithine transcarbamylase deficiency (OTCD) utilizing 1H MRS. Methods Single voxel 1H 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 19–59 years; average 34 years; controls ranged from 18–59 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 [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.

Switch from Sodium Phenylbutyrate to Glycerol Phenylbutyrate Improved Metabolic Stability in an Adolescent with Ornithine Transcarbamylase Deficiency

“…Hyperammonemia-related neurological injuries range from lethal cerebral edema to mild or subclinical cognitive impairment, depending on the severity of the defect (Gropman et al 2008), with the most severely affected patients typically presenting early in life (Brusilow and Maestri 1996;Summar et al 2008;Tuchman et al 2008). Ornithine transcarbamylase (OTC) deficiency is the most common UCD, accounting for slightly more than half of all UCD cases (Summar et al 2008;Tuchman et al 2008;Batshaw et al 2014).…”

Creatine as Biomarker

“…Moreover, decreased brain Cr content was reported, in one patient with ASS, by Choi and Yoo (2001). On the contrary, other authors found normal cerebral Cr content in patients with OTC deficiency (Choi and Yoo 2001;Takanashi et al 2002;Gropman et al 2008), but it should be taken into account that probably H 1 -NMR brain spectroscopy is not the best method to show slight Cr decreases. Arginase deficiency (MIM#207800) is one of the most infrequent UCD; biochemically, this disease is characterized by hyperargininemia.…”

Intracranial Pressure Monitoring Demonstrates that Cerebral Edema Is Not Correlated to Hyperammonemia in a Child with Ornithine Transcarbamylase Deficiency

“…In older children, peak ammonia levels are generally lower but remains >200 mmol/ L in most of the patients during acute crises (Enns et al 2007). However, severe neurological crises have been reported even in the absence of severe hyperammonemia (Kojic et al 2005;Mak et al 2007;Gropman et al 2008). This apparent discrepancy between neurological impairment and plasma ammonia level may be explained in part by the mechanisms of hyperammonemia neurotoxicity.…”

“…This can be achieved using an analysis program such as "LCModel," but this step needs most of the time the assistance of a specialist. The use and the accuracy of this method have been clearly validated to evaluate brain metabolism in OTCD patients (see Gropman et al 2008) for details), but this investigation cannot be regularly repeated (Connelly et al 1993). In contrast, continuous ICP monitoring was very useful to detect ICP peaks and to treat them immediately, in the aim to maintain adequate CPP and to prevent cerebral damages.…”

“…Classically in children with urea cycle disorders (UCD), hyperammonemic encephalopathy is associated with severe hyperammonemia, and its management is based on the follow-up of plasma ammonia level (Haberle et al 2012). However, ammonia level is not a reliable tool to predict raised ICP, and severe neurological crises have been reported in some patients with only mild increase in plasma ammonia level, suggesting that brain glutamine level will be a better marker of cerebral dysfunction than blood ammonia or glutamine levels (Kojic et al 2005;Mak et al 2007;Gropman et al 2008). Brain glutamine level may be estimated by analysis of cerebrospinal fluid obtained by lumbar puncture or by brain magnetic resonance spectroscopy.…”