Background: Rab-GDI mutations are responsible for "pure" mental deficiency, without any specific clinical features or brain malformation. Therefore, screening for mutations in mentally retarded patients is not available on a routine basis. Moreover, neuronal networks involved in mental deficiency still remain largely unknown.
Methods: We performed a fine neuropsychological and imaging study in five patients from two unrelated families, affected with mental deficiency due to a mutation in the Rab-GDI gene. High resolution 3D brain MRI of the five mentally retarded adult males (mean age 33 years) were compared to MRI of 14 healthy males (mean age 35 years) using a Voxel-Based Morphometric analysis (VBM).
Results: All patients had isolated moderate mental retardation (WAIS-III IQ range, 41-50; mean 45) without specific morphological or behavioural features. No obvious brain abnormality was observed on visual inspection of individual scans. Using VBM analysis, Rab-GDI mutated patients' MRIs exhibited significant brain changes compared to normal subjects (p<0.05, corrected for multiple comparisons): increased grey matter density in left cerebellum and in left angular gyrus, decreased grey matter volume in thalami, decreased white matter density in prefrontal lobes, right fusiform occipito-temporal gyrus, and decreased white matter volume in cerebellar peduncles.
Conclusions: These morphological changes observed in Rab-GDI mutated patients, mainly localized in the cerebello-thalamo-prefrontal pathway, are consistent with the hypothesis that the cerebellum is one of the critical components of a global learning network. Our results open new avenues in the diagnosis of non-specific mental deficiency using gene-specific "brain maps" as endophenotypes.