Brain morphometry and cognition in late-onset glutaric aciduria type 1: scoping review and novel insights from a case report

Introduction Glutaric Aciduria type I (GA1) is a rare autosomal recessive organic aciduria, with typical early-onset presentation, characterized by severe movement disorders with damage to the basal ganglia following an acute encephalopathic crisis. Late-onset (LO), milder forms have rarely been described. In LO patients, severe brain damage is frequently reported, including frontotemporal hypoplasia, brain atrophy, subependymal nodules and leukodystrophy. Cognitive impairment is sometimes described, often without formal psychometric assessment. Objectives This scoping review aims to synthesize the neuroradiological and neuropsychological features of all LO GA1 patients reported in the literature to date, divided in undiagnosed LO cases detected through selective screening and LO cases with onset of symptoms after 6 years of age. Methods The following databases were used: PubMed, Embase and Medline. The search strategy abides by the PRISMA-ScR guidelines. Results Out of the 53 LO patients reviewed, extensive quantitative neuropsychological testing was reported in seven cases, while no brain morphometric analysis was performed. Case report CASE REPORT. A novel case of a GA1 34-year-old Chinese woman identified through the neonatal screening of her healthy baby is described. Brain morphometric analysis showed diffused reduced volumes and cortical thinning, involving fronto-temporal areas and, to a lesser extent, the parieto-occipital regions. The neuropsychological assessment highlighted mild difficulties in verbal executive functions (inferential thinking) and phonological shortterm memory. Conclusion The present review and case report suggest that integrating neuroanatomical and neuropsychological investigations into clinical practice may allow a more refined characterization of GA1 patients, contributing to unveil the complex ethio-pathogenic mechanisms underlying the disease and monitor patients over time.