Neurocognitive and neuroradiological findings and their association in a Spanish Pediatric cohort with glutaric aciduria type 1

Abstract Background This study aimed to characterize the neurocognitive and neuroradiological profiles of children and young adults with Glutaric Aciduria Type 1 (GA-1) included in the Spanish National GA-1 Registry and to examine the association between MRI abnormalities and neurocognitive performance. Methods This national multicenter registry-based study included 53 unique patients with GA-1 recruited between 2019 and 2022, who contributed 61 neurocognitive assessment occasions. Neurocognitive and neuroradiological assessments were centralized at Hospital Universitario 12 de Octubre and performed using age-appropriate standardized instruments and a centralized MRI protocol. Results Neurocognitive assessment showed generally preserved global cognitive functioning, with selective vulnerabilities in fine motor skills, attention, processing speed, executive functioning, working memory, and visuocognitive processes, particularly in participants aged 4 years or older. Structural MRI data were available for 38 unique patients, corresponding to 45 MRI assessment occasions; 28/45 MRI examinations (62.2%) showed at least one neuroradiological abnormality. Striatal involvement was present in 21/28 abnormal MRI examinations (75%), while extrastriatal abnormalities included impaired/incomplete opercularization, white-matter signal abnormalities, white-matter diffusion restriction, and dentate nucleus involvement. Exploratory comparisons suggested poorer neurocognitive performance in participants with striatal or combined MRI abnormalities. Conclusions Children and young adults with GA-1 may present selective neurocognitive vulnerabilities despite relatively preserved global cognitive functioning. Both striatal and extrastriatal MRI abnormalities should be considered when interpreting the neurodevelopmental phenotype. These findings support multidisciplinary follow-up and longitudinal neuropsychological surveillance as higher-order cognitive functions emerge across development, although the present study was not designed to determine the independent effects of early diagnosis, treatment, or multidisciplinary monitoring on neurocognitive outcome.