This case series analyzed brain morphology in 11 patients (ages 2 to 19 years) with NGLY1 Deficiency, an ultra-rare disorder. Researchers analyzed 16 real-world MRI scans performed globally, comparing them to normative models from CentileBrain for patients over 3 years old or custom models for those under 3. The primary outcome was cortical and subcortical morphology, including volume, thickness, surface area, and curvature.
Main results showed significantly reduced subcortical volumes. In younger patients (<3 years), there were widespread reductions in cortical surface area, volume, and curvature. In older patients (>3 years), cortical patterns were mixed, with thinner dorsal and thicker ventral regions and limited surface area reductions. Secondary analyses found correlations: in older patients, thalamic volume reduction correlated with gait disturbance, dysphagia, and EEG abnormalities. In younger patients, seizure presence correlated with altered cortical thickness, surface area, and curvature patterns. No statistical measures (p-values, effect sizes, absolute numbers) were reported for these findings.
Safety and tolerability data were not reported. Key limitations include the ultra-rare nature of the disorder (~165 patients worldwide), the small sample size of 11 patients, and the case series design, which shows association, not causation. The study was observational. The authors suggest these morphological measures may serve as useful biomarkers for tracking disease progression or treatment efficacy, but this remains hypothetical. For clinicians, these findings describe the neuroanatomical landscape of NGLY1 Deficiency but do not support changes to clinical management.
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Importance: NGLY1 (N-Glycanase 1) Deficiency is an ultra-rare 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. Objective: To investigate alterations in brain morphology in patients with NGLY1 Deficiency and determine whether these metrics associate with clinical phenotypes. Design, Setting, and Participants: This case series analyzed real-world MRI scans performed on 11 patients with NGLY1 Deficiency between 1999-2023 at sites across the globe. Ages ranged from 2 to 19 years at scan time (5 female, 6 male). Exposure: Molecular diagnosis of NGLY1 Deficiency. Main Outcomes and Measures: Cortical and subcortical morphology, including subcortical volume, and cortical thickness, surface area, volume, and curvature, were measured with 3-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. Results: 16 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. Conclusions and Relevance: 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 ultra-rare disorder.
