Brain Biomarkers of Long-Term Outcome of Neonatal Onset Urea Cycle Disorder

Maha Mourad,Johannes Häberle,Matthew Whitehead,Tamar Stricker,Andrea Gropman

doi:10.3390/ijns2040010

Abstract

Urea cycle disorders (UCDs) are common inborn errors of metabolism, with an incidence of one in 30,000 births. They are caused by deficiencies in any of six enzymes and two carrier proteins, the most common being Ornithine Transcarbamylase Deficiency (OTCD). OTCD results in impairment to excrete nitrogen, causing toxic buildup of ammonia with resultant encephalopathy. Hyperammonemia (HA) induces the conversion of glutamate to glutamine in the brain. Excess glutamine in the brain causes osmotic changes, cerebral edema, changes in astrocyte morphology, and cell death. Acute symptoms of HA include vomiting, hyperventilation, seizures, and irritability. Long-term neurological effects include deficits in working memory and executive function. To date, there are no predictors of prognosis of infants with neonatal onset OTCD outside of the plasma ammonia level at presentation and duration of a hyperammonemic coma. We provide a comprehensive analysis of a 16-year-old male with neonatal onset of OTCD as an example of how brain biomarkers may be useful to monitor disease course and outcome. This male presented at 8 days of life with plasma ammonia and glutamine of 677 and 4024 micromol/L respectively, and was found to have a missense mutation in Exon 4 (p. R129H). Treatment included protein restriction, sodium benzoate, and citrulline, arginine, and iron. Despite compliance, he suffered recurrent acute hyperammonemic episodes triggered by infections or catabolic stressors. We discuss the long-term effects of the hyperammonemic episodes by following MRI-based disease biomarkers.

Highlights

The urea cycle disorders (UCDs) represent a group of rare inborn errors of metabolism characterized by a defect in the metabolism of waste nitrogen from the breakdown of protein and other nitrogen-containing molecules (Figure 1) [1,2]
Plasma glutamine and ammonia levels were not always correlated with one another and glutamine increase may precede the development of hyperammonemic event (HA)
Plasma glutamine and brain glutamine levels both remained elevated during the HA episode even after plasma ammonia levels return to normal following a hyperammonemic episode

Summary

Introduction

The urea cycle disorders (UCDs) represent a group of rare inborn errors of metabolism characterized by a defect in the metabolism of waste nitrogen from the breakdown of protein and other nitrogen-containing molecules (Figure 1) [1,2]. Severe deficiency or total absence of activity of any of the first four enzymes in the urea cycle (Carbamoyl phosphate Synthetase 1, CPS1; Ornithine transcarbamylase, OTC; Argininosuccinate Synthetase, ASS; and Argininosuccinate Lyase, ASL) or the cofactor producer (N-Acetyl glutamate Synthase, NAGS) results in the accumulation of ammonia and other precursors. Proximal UCDs (CPS1, NAGs and OTC deficiencies) lead to accumulation of ammonia and glutaPmroinxeim(agllnU),CwDshi(cChPSm1a,yNbAeGtsoaxnicd pOroTdCudctesficoifenpcrioetse)inleamdettoabaoclcisummuwlahteionn eolfevaamtemdo[n3i]a. STehdesine dtheefipcirtesfcroonnttarilbcuotretesxig(nPiFfiCca),nstulychtoadsiwsaobrikliitny.g memory, executive cognition and attenNtioeunr[o7i–m9]a.gTinhgesecadnefhiceiltps cuosntprirboubtee smiganrikfeicrasnotlfyntoeudrioslaobgiliictayl. AFguinncgtio(MnaRl IM) RcaIn(fMdeRmI)oannsdtrwatheitme imcraotstecor ptriacctaongartaopmhiyc hdealmp aognee tthoautnpdreecrsetdaensdchlionwicatlhseybmrapitnocmosns[1tr0u].ctFsunnecutiroanl anleMtwRoIrk(fsMtoRIp)earnfodrmwhciotgenmitaivtteetratsrkasctaongdrahpohwy thheelspe onneetwtoorukns dareersatlatnerdedhoinwbtrhaeinbdriasionrdcoenrsstarnudctrsecnoevuerrayl [n7e–t9w,1o1r,k1s2]t.o perform cognitive tasks and howMthaegsneenteictwreosroknsaanrceeaslpteercetdroisncobprayin(MdRisSo)rdcaenrsaallnodwreqcuoavnetritya[t7iv–e9,s1a1m,1p2l]i.ng of regional, focal, and globaMl cahgannetgiecsreinsomnaentcaebospliescmtrowscitohpyre(gMarRdS)tocapnraecllloinwicqaul acnhtaitnagtievseasnadmprelisnpgonofseretgoiotnhaelr,afpoiceasl,[a1n3d]. Rgleocboaglncithioanngoefsainnummebtearboofliisnmviwvoithneruergoairmdatgoinpgretecclihnniciqaluecsh,awngheicshacnadn rreeslipaobnlyseantod tnhoenrianpvieassiv[1e3ly]. aRsesceossgnaistpioenctsofoaf nneuumrobaenraotfominyv, icvhoemneiustrroyi,mphagyisnioglotegcyh, nainqduepsa,twhohliocghy,cahnolrdelpiarobmlyiasendasnboinoimnvaarksievres.ly assess aspects of neuroanatomy, chemistry, physiology, and pathology, hold promise as biomarkers

Patient and Methods

Neuroimaging Collection

Results

Conclusions