Brain imaging as a prognostic biomarker in urea cycle disorders

The Urea cycle disorders (UCDs) represent a group of rare inborn errors of metabolism that have impaired nitrogen handling from the breakdown of protein, with ensuing acute episodic or chronic hyperammonemia and neurotoxicity. Although advances in newborn screening, molecular diagnosis, and therapeutic interventions have improved survival, neurocognitive, behavioral, and psychiatric sequelae remain prevalent in those with both neonatal onset as well as later onset partial deficiencies. The mechanisms of brain injury in UCDs are complex and multifactorial, and in some cases are not fully known. Common themes include astrocytic dysfunction, altered neurotransmitter cycling, oxidative stress, and energy failure. Neuromonitoring including EEG and Neuroimaging has become a cornerstone in elucidating these mechanisms in UCD patients, offering objective biomarkers to detect subclinical injury, guide management, and evaluate treatment efficacy. This review synthesizes current neuroimaging therapies used in routine clinical practice (structural MRI, Diffusion imaging), as well as research focused and emerging imaging modalities including magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), functional MRI (fMRI), and functional near-infrared spectroscopy (fNIRS) and discusses their translational potential beyond diagnostic entities as prognostic and therapeutic biomarkers in UCDs. Novel approaches such as glutamine chemical exchange saturation transfer (GlnCEST) imaging and multimodal integration with omics data may offer a framework for predictive modeling and precision-guided care. The validation of imaging biomarkers across multicenter studies and across field strengths represents a critical next step in the evolution of neuroimaging from descriptive to quantitative, prognostic, and regulatory endpoints in metabolic disorders. Important issues in multicenter harmonization will be addressed but not discussed in detail.