Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder characterized by arylsulfatase A (ASA) deficiency, leading to sulfatide accumulation and myelin degeneration in the central nervous system. While primarily considered a white matter (WM) disease, gray matter (GM) is also affected in MLD, and hematopoietic stem cell transplantation (HSCT) may have limited effect on GM atrophy. We cross-sectionally and longitudinally studied GM volumes using volumetric MRI in a cohort of 36 (late-infantile, juvenile and adult type) MLD patients containing untreated and HSCT treated subjects. Cerebrum, cortical GM, (total) CSF, cerebellum, deep gray matter (DGM) (excluding thalamus) and thalamus volumes were analyzed. Longitudinal correlations with measures of cognitive and motor functioning were assessed. Cross-sectionally, juvenile and adult type patients (infantiles excluded based on limited numbers) were compared with controls at earliest scan, before possible treatment. Patients had lower cerebrum, cortical GM, DGM and thalamus volumes. Differences were most pronounced for adult type patients. Longitudinal analyses showed substantial and progressive atrophy of all regions and increase of CSF in untreated patients. Similar, albeit less pronounced, effects were seen in treated patients for cerebrum, cortical GM, CSF and thalamus volumes. Deterioration in motor performance (all patients) was related to atrophy, and increase of CSF, in all regions. Cognitive functioning (data available for treated patients) was related to cerebral, cortical GM and thalamus atrophy; and to CSF increase. Our findings illustrate the importance of recognizing GM pathology as a potentially substantial, clinically relevant part of MLD, apparently less amenable to treatment.
Keywords: HSCT; MLD; MRI; atrophy; gray matter; leukodystrophy.
© 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.