SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage

Abstract

SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration.

Keywords: ACE-R, Addenbrooke's Cognitive Examination Revised; ALS, amyotrophic lateral sclerosis; CA, cord area; CE, cord eccentricity; CMAP, compound muscle action potential; CST, corticospinal tract; Complicated hereditary spastic paraplegia; DTI, diffusion tensor imaging; FA, fractional anisotropy; GM, grey matter; Grey matter; HSP, hereditary spastic paraplegia; LH, left hemisphere; MD, mean diffusivity; MOCA, Montreal cognitive assessment; Motor neuron disorder; NPI, neuropsychiatric inventory; PNP, sensory-motor polyneuropathy; PNS, peripheral nervous system; RH, right hemisphere; ROI, region of interest; SC, spinal cord; SNAP, sensory nerve action potential; SPG11; SPRS, Spastic Paraplegia Rating Scale; STS, cortex adjacent to the superior temporal sulcus; Spinal cord; Thinning of the corpus callosum; WES, whole exome sequencing; WM, white matter; White matter.

Fig. 1

Frequencies of phenotypic traits identified in 25 SPG11 patients.

Fig. 2

Axial MR showing regions with significant GM damage in SPG11, areas are color-coded (from red to yellow). ROI-based analyses using T1 multi-atlas approach to assess deep GM volumes; FreeSurfer analyses of cortical regions as defined by Desikan et al. (2006) to assess cortical thickness. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Results of multi-atlas approach showing areas of reduced fractional anisotropy (FA) and increased axial diffusivity (AD), mean diffusivity (MD) and radial diffusivity (RD) in patients with SPG11 after comparison with controls, areas are color-coded (from red to yellow). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)