Abstract
Spastic paraplegia type 7 (SPG7), which represents one of the most common forms of autosomal recessive spastic paraplegia (MIM#607259), often manifests with a complicated phenotype, characterized by progressive spastic ataxia with evidence of cerebellar atrophy on brain MRI. Recent studies have documented the presence of peculiar dentate nucleus hyperintensities on T2-weighted images and frontal executive dysfunction in neuropsychological tests in SPG7 patients. Therefore, we decided to assess whether any particular MRI pattern might be specifically associated with SPG7 mutations and possibly correlated with patients' cognitive profiles. For this purpose, we evaluated six SPG7 patients, studying the cerebello-cortical network by MRI voxel-based morphometry and functional connectivity techniques, compared to 30 healthy control subjects. In parallel, we investigated the cognitive and social functioning of the SPG7 patients. Our results document specific cognitive alterations in language, verbal memory, and executive function in addition to an impairment of social task and emotional functions. The MRI scans showed a diffuse symmetric reduction in the cerebellar gray matter of the right lobule V, right Crus I, and bilateral lobule VI, together with a cerebral gray matter reduction in the lingual gyrus, precuneus, thalamus, and superior frontal gyrus. The evidence of an over-connectivity pattern between both the right and left cerebellar dentate nuclei and specific cerebral regions (the lateral occipital cortex, precuneus, left supramarginal gyrus, and left superior parietal lobule) confirms the presence of cerebello-cortical dysregulation in different networks involved in cognition and social functioning in SPG7 patients.
Highlights
Mutations in the spastic paraplegia type 7 (SPG7) gene, encoding the mitochondrial protein paraplegin (MIM∗602783), are responsible for a rare form of hereditary spastic paraplegia [1, 2] and are usually transmitted as an autosomal recessive trait, which can cause both pure and complex phenotypes [1]
The dentate nucleus (DN) is the major cerebellar output channel connecting to the cerebral cortex [8], and modifications in functional connectivity (FC) within specific cerebello-cortical networks have already been described in patients affected by other forms of cerebellar atrophy [9,10,11,12] and linked to motor, cognitive, and behavioral symptoms [13,14,15,16,17,18,19,20,21,22]
The SPG7 group return pathological results in the Theory of Mind (ToM) (66% of SPG7 patients), the RME total scores (83% of patients), and the “embarrassed” emotion of the Emotion Attribution test (EA) test (100% of patients), while no differences compared to normative data were observed in the other emotions
Summary
Mutations in the spastic paraplegia type 7 (SPG7) gene, encoding the mitochondrial protein paraplegin (MIM∗602783), are responsible for a rare form of hereditary spastic paraplegia [1, 2] and are usually transmitted as an autosomal recessive trait, which can cause both pure and complex phenotypes [1]. Despite the fact that cerebellar degeneration is a hallmark of the SPG7 complex phenotype, to date, only a few studies have attempted to characterize the pattern of cerebellar involvement in correlation with other brain structures. In this regard, Hewamadduma et al [7] proposed cerebellar vermis atrophy associated with an increase in the T2 signal on MRI images of the dentate nucleus (DN) as a possible specific MRI pattern in SPG7 [7]. The DN is the major cerebellar output channel connecting to the cerebral cortex [8], and modifications in functional connectivity (FC) within specific cerebello-cortical networks have already been described in patients affected by other forms of cerebellar atrophy [9,10,11,12] and linked to motor, cognitive, and behavioral symptoms [13,14,15,16,17,18,19,20,21,22]
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