MRI Characterization of Structural Brain Abnormalities in NGLY1 Deficiency.

BACKGROUND AND

objectivesNGLY1 (N-Glycanase 1) deficiency is an ultrarare autosomal recessive disorder affecting ~165 patients worldwide, characterized by developmental delay, hyperkinetic movement disorders and shortened life expectancy. Despite its severe neurological manifestations, comprehensive neuroimaging characterization has been limited to case reports and small descriptive studies. Our objective was to investigate alterations in brain morphology in patients with NGLY1 deficiency and determine whether these metrics associate with clinical phenotypes.

methodsThis case series analysed real-world MRI scans performed on 11 patients with molecularly diagnosed NGLY1 deficiency between 1999 and 2023 at sites across the globe. Ages ranged from 2 to 19 years at scan time (five female and six male). Cortical and subcortical morphology, including subcortical volume and cortical thickness, surface area, volume and curvature, was measured with three-dimensional T1-weighted magnetic resonance imaging (MRI) scans. Z scores were calculated using normative models from CentileBrain for patients > 3 years old or custom models for patients < 3 years old. Clinical phenotypes were matched to Human Phenotype Ontology codes.

resultsSixteen scans from 11 patients met quality criteria for analysis. Both age groups (under and over 3 years old) showed significantly reduced subcortical volumes, particularly in bilateral thalamus and putamen. Younger patients demonstrated widespread reductions in cortical surface area, volume and curvature, indicating altered gyrification patterns. Older patients showed thinner dorsal and thicker ventral cortical regions with limited surface area reductions. Thalamic volume reduction in older patients correlated with gait disturbance, dysphagia and EEG abnormalities, with additional cortical associations with sleep and hearing abnormalities. Seizure presence in younger patients correlated with altered cortical thickness, surface area and curvature patterns. DISCUSSION: NGLY1 deficiency is associated with pervasive alterations in brain development affecting both subcortical and cortical morphology. Age-dependent patterns of cortical alterations indicate disrupted neurodevelopmental trajectories that may reflect impaired neuronal migration and/or altered synaptic pruning. Correlations with clinical variables suggest that these measures may serve as useful biomarkers for tracking disease progression and/or treatment efficacy. These findings provide a comprehensive neuroimaging characterization of NGLY1 Deficiency and establish a foundation for understanding brain structure-function relationships in this ultrarare disorder.